CN107690431A - Aryl sultam derivative as RORc conditioning agents - Google Patents

Aryl sultam derivative as RORc conditioning agents Download PDF

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Publication number
CN107690431A
CN107690431A CN201680033181.5A CN201680033181A CN107690431A CN 107690431 A CN107690431 A CN 107690431A CN 201680033181 A CN201680033181 A CN 201680033181A CN 107690431 A CN107690431 A CN 107690431A
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CN
China
Prior art keywords
alkyl
formulas
carbonyl
amino
alkoxy
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Chinese (zh)
Inventor
B·法贝尔
E·甘西亚
T·拉杜瓦赫蒂
D·维赛
P·温希普
O·勒内
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Publication of CN107690431A publication Critical patent/CN107690431A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention discloses compound of formula I or its pharmaceutically useful salt, wherein m, n, p, q, r, X1、X2、X3、X4、Y、Z、A、Het、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12And R13As defined herein.Method the invention also discloses the preparation method of the compound and using the compounds for treating inflammatory disease, the disease is such as arthritis, muscle gelling and psoriasis.

Description

Aryl sultam derivative as RORc conditioning agents
The present invention relates to the chemical combination for the function that can adjust the related orphan receptor RORc (ROR γ) of retinoids-acceptor The purposes of thing and such compound in autoimmune disease is treated.
T aids in the CD4+T cells that 17 cells (Th17) are secretion interleukins (IL) -17, the morbidity with autoimmune disease Mechanism is relevant, and the disease such as rheumatoid arthritis, IBS, psoriasis, psoriatic arthritis and vertebra close Section is scorching.The related orphan receptor γ (ROR γ or RORc) of retinoic acid is considered as the transcription factor required for Th17 cell differentiations. RORc is the orphan member of nuclear hormone receptor subfamily, including ROR α (RORa) and ROR β (RORb).RORc passes through as monomer With DNA with reference to and control genetic transcription.RORc selective control to be considered as discovery related to exploitation Th17 cells itself The approach of immunological diseases.
It is therefore desirable to be able to suppress RORc compound, for treating autoimmune disease, such as rheumatoid joint Inflammation, osteoarthritis, psoriatic arthritis, IBS, asthma, COPD, psoriasis, lupus, She Gelunshi diseases, idiopathic Pulmonary fibrosis, muscle gelling and arthritis vertebralis.
The invention provides compound of formula I or its pharmaceutically useful salt：
Wherein：
M is 0 or 1；
N is 0 or 1；
P is 0-3；
Q is 0,1 or 2；
R is 1,2 or 3；
A is：
Key；
-(CRjRk)t-；
-C(O)-(CRjRk)t-；
-(CRjRk)t-C(O)-；
-NRa-(CRjRk)t-；
-(CRjRk)t-NRa-；
-C(O)NRa-(CRjRk)t-；
-(CRjRk)t-NRaC(O)-；
-O-(CRjRk)t-；
-(CRjRk)t-O-；
-S-(CRjRk)t-；
-(CRjRk)t-S-；
-SO2-(CRjRk)t-；
-(CRjRk)t-SO2-；Or
T is 0-4；
W is：
-CRbRc-；
-O-；
-S-；
-SO2-；Or
-NRd-；
X1、X2、X3And X4One of be N, remaining is CRe；
Or X1、X2、X3And X4In two be N, remaining is CRe；
Or X1、X2、X3And X4In three be N, another is CRe；
Or each X1、X2、X3And X4For CRe；
Y is：
-O-；
-S-；
-SO2-；
-CRfRg-；Or
-NRh-；
Z is：
Key；
-C1-6Alkylidene-；
-NRp-C1-6Alkylidene；
-C1-6Alkylidene-NRp-；
-NRp-；
-C(O)-；
-C(O)NRp-；
-C(O)NRp-C1-6Alkylidene；
-NRpC(O)-；
-NRpC(O)-C1-6Alkylidene；
-C1-6Alkylidene-O-；
-O-C1-6Alkylidene-；Or
-C1-6Alkylidene-O-C1-6Alkylidene-；
Het is：
Heteroaryl, it is selected from：
Oxazolyl；
Isoxazolyl；
Thiazolyl；
Isothiazolyl；
Pyrazolyl；
Triazolyl；
Oxadiazolyl；
Thiadiazolyl group；
Pyridine radicals；
Pyrimidine radicals；
Pyrazinyl；Or
Imidazole radicals；
Wherein each heteroaryl can be unsubstituted or by RmSubstitution is one or more times；Or
Heterocyclic radical, it is selected from：
Oxetanylmethoxy；
Tetrahydrofuran base；
THP trtrahydropyranyl；
Pyrrolidinyl；
Piperidyl；
Piperazinyl；
Oxazole alkyl；
Imidazolidinyl；
Morpholinyl；
Thio-morpholinyl；Or
1,1- dioxothiomorpholinyls；
Wherein each heterocyclic radical can be unsubstituted or by RnSubstitution is one or more times；
R1、R2、R3、R4、R5、R6、R7And R8Each stand alone as：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Or R3And R4Ethylidene is formed together with the atom connected with them；
Or R3And R4It can be formed together with the atom connected with them 3,4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R5And R6It can be formed together with the atom connected with them 3,4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R7And R8It can be formed together with the atom connected with them 3,4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R3And R4One of and R5And R6One of and their atoms for being connected can form 3,4,5,6 or 7 yuan together Saturation or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can appoint Choosing is by RiSubstitution is one or more times；
Or R5And R6One of and R7And R8One of and their atoms for being connected can form 3,4,5,6 or 7 yuan together Saturation or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can appoint Choosing is by RiSubstitution is one or more times；
Each R9Stand alone as：
C1-6Alkyl；
Halogen；
C1-6Alkoxy；Or
Cyano group；
Wherein C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；
R10For：
Hydrogen；
Carboxyl；
C1-6Alkyl-carbonyl；
C1-6Alkoxy-carbonyl；
Oxo；
Hydroxyl；
Amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Cyano group；
Hydroxyl-C1-6Alkyl；
N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl；
N- hydroxyls-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-amino carbonyl；
Halogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times or oxo；
R11For：
Hydrogen；
Halogen；
Carboxyl；
C1-6Alkyl-carbonyl；
C1-6Alkoxy-carbonyl；
Oxo；
Hydroxyl；
Amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
C1-6Alkyl-sulfonylamino；
C1-6Alkyl-sulfonylamino-C1-6Alkyl；
Cyano group；
Hydroxyl-C1-6Alkyl；
N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl；
N- hydroxyls-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-amino carbonyl；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times or oxo；
Or R10And R11Can be formed together with the atom connected with them 3,4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitute one or more It is secondary；
Or R10And R11Double bond is formed together with the atom connected with them；
R12For：
Hydrogen；
Halogen；
Carboxyl；
C1-6Alkyl-carbonyl；
C1-6Alkoxy-carbonyl；
Oxo；
Hydroxyl；
Amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Cyano group；
Hydroxyl-C1-6Alkyl；
N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl；
N- hydroxyls-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-amino carbonyl；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times or oxo；
R13For：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Ra、Rb、RcAnd RdEach stand alone as：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Or RbAnd RcIt can be formed together with the atom connected with them 3,4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or RbAnd RcOne of and R7And R8One of and their atoms for being connected can form 3,4,5,6 or 7 yuan together Saturation or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can appoint Choosing is by RiSubstitution is one or more times；
Or RbAnd RcOne of and R5And R6One of and their atoms for being connected can form 3,4,5,6 or 7 yuan together Saturation or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can appoint Choosing is by RiSubstitution is one or more times；
Each ReStand alone as：
Hydrogen；
C1-6Alkyl；
Halogen；
C1-6Alkoxy；Or
Cyano group；
Wherein C1-6Moieties can be unsubstituted or by halogen, hydroxyl or C1-6Alkoxy substitutes one or more times；
RfFor：
Hydrogen；
Halogen；
C1-6Alkoxy；Or
C1-6Alkyl, it can be unsubstituted or by halogen, hydroxyl or C1-6Alkoxy substitutes one or more times；
RgFor：
Hydrogen；
C1-6Alkyl；
C3-6Cycloalkyl, it can be unsubstituted or by C1-6Alkyl substitution is once or secondary；
C2-6Alkenyl；
C3-6Cycloalkenyl group；
C3-6Cycloalkyl-C1-6Alkyl；
Halogen；
C1-6Alkyl-carbonyl；
C3-6Cycloalkyl-carbonyl；
C3-6Cycloalkyl-C1-6Alkyl-carbonyl；
Cyano group-C1-6Alkyl-carbonyl；
Hydroxyl-C1-6Alkyl-carbonyl；
C1-6Alkoxy -C1-6Alkyl-carbonyl；
Carboxyl；
N- cyano group-amino carbonyl；
N- cyano group-N-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkyl-ethanamidine base (acetimidamidyl)；
N, N '-two-C1-6Alkyl-ethanamidine base；
N '-cyano group-N-C1-6Alkyl-ethanamidine base；
N'- hydroxy-acetamidine bases；
N'-C1-6Alkoxy-ethanamidine base；
N'- hydroxy-ns-C1-6Alkyl-ethanamidine base；
N'-C1-6Alkoxy-N-C1-6Alkyl-ethanamidine base；
2- nitros -1-N-C1-6Alkyl amino-vinyl；Formoxyl；
C1-6Alkyl-sulfonyl base；
C3-6Cycloalkyl-sulfonyl；
C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；
C1-6Alkyl-sulfonyl base-C1-6Alkyl；
Amino carbonyl；
Carbonylamino；
N- hydroxy-amino carbonyls；
N-C1-6Alkoxy-amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
Amino carbonyl-C1-6Alkyl；
N-C1-6Alkyl-aminocarbonyl-C1-6Alkyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl-C1-6Alkyl；
C1-6Alkoxy-carbonyl；
N- hydroxy-ns-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Amino-sulfonyl；
N-C1-6Alkyl-amino sulfonyl；
- the C of N, N- bis-1-6Alkyl-amino sulfonyl；
Cyano group；
C1-6Alkoxy；
C1-6Alkyl-sulfonylamino；
N-C1-6Alkyl-sulfonylamino carbonyl；
N-(C1-6Alkyl-sulfonyl base)-N-C1-6Alkyl-aminocarbonyl；
N-(C1-6Alkyl-sulfonyl base)-amino-C1-6Alkyl；Amino；
N-C1-6Alkyl-amino；
- the C of N, N- bis-1-6Alkyl-amino；
Halo-C1-6Alkyl；
Phenyl；
Heterocyclic radical；
Heteroaryl；
C1-6Alkyl-carbonylamino；
Carbonylamino；Or
Hydroxyl；
Wherein C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；
Wherein phenyl, heterocyclic radical, heteroaryl, C3-6Cycloalkyl, C3-6Cycloalkenyl group and C3-6Cycloalkyl-C1-6Moieties can be with It is unsubstituted or by RiSubstitution is one or more times；
Or RfAnd RgOxo can be formed together；
Or RfAnd RgIt can be formed together with the atom connected with them 4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
RhFor：
Hydrogen；
C1-6Alkyl；
C3-6Cycloalkyl；
C3-6Cycloalkenyl group；
C3-6Cycloalkyl-C1-6Alkyl；
C1-6Alkyl-carbonyl；
C3-6Cycloalkyl-carbonyl；
C3-6Cycloalkyl-C1-6Alkyl-carbonyl；
Cyano group-C1-6Alkyl-carbonyl；
Hydroxyl-C1-6Alkyl-carbonyl；
C1-6Alkoxy -C1-6Alkyl-carbonyl；
N- cyano group-amino carbonyl；
N- cyano group-N-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkyl-ethanamidine base；
N, N '-two-C1-6Alkyl-ethanamidine base；
N '-cyano group-N-C1-6Alkyl-ethanamidine base；
N'- hydroxy-acetamidine bases；
N'-C1-6Alkoxy-ethanamidine base；
N'- hydroxy-ns-C1-6Alkyl-ethanamidine base；
N'-C1-6Alkoxy-N-C1-6Alkyl-ethanamidine base；
2- nitros -1-N-C1-6Alkyl amino-vinyl；
Formoxyl；
C1-6Alkyl-sulfonyl base；
C3-6Cycloalkyl-sulfonyl；
C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；
C1-6Alkyl-sulfonyl base-C1-6Alkyl；
Amino carbonyl；
N- hydroxy-amino carbonyls；
N-C1-6Alkoxy-amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
N- hydroxy-ns-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Amino-sulfonyl；
N-C1-6Alkyl-amino sulfonyl；
- the C of N, N- bis-1-6Alkyl-amino sulfonyl；
Cyano group；
C1-6Alkyl-sulfonylamino；
C1-6Alkyl-sulfonylamino-C1-6Alkyl；
N-(C1-6Alkyl-sulfonyl base) amino carbonyl；
N-(C1-6Alkyl-sulfonyl base)-N-C1-6Alkyl-aminocarbonyl；
N-(C1-6Alkyl-sulfonyl base)-amino-C1-6Alkyl；
Amino carbonyl-C1-6Alkyl；
N-C1-6Alkyl-aminocarbonyl-C1-6Alkyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl-C1-6Alkyl；
C1-6Alkoxy-carbonyl；
Phenyl；
Heterocyclic radical；Or
Heteroaryl；
Wherein C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；
Wherein phenyl, heterocyclic radical, heteroaryl, C3-6Cycloalkyl, C3-6Cycloalkenyl group and C3-6Cycloalkyl-C1-6Moieties can be with It is unsubstituted or by RiSubstitution is one or more times；
Or RhWith R10And R11One of 4,5,6 or 7 yuan of aromatics, saturation can be formed together with the atom that they are connected Or the ring of fractional saturation, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- other hetero atoms, it can be optional By-RiSubstitution is one or more times；
Or RfAnd RgOne of and R10And R11One of and their atoms for being connected can form 3,4,5,6 or 7 together First aromatics, saturation or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- other miscellaneous originals Son, it can be optionally by RiSubstitution is one or more times；
RiFor：
C1-6Alkyl；
Halo-C1-6Alkyl；
C3-6Cycloalkyl；
Halogen；
Oxo；
Hydroxyl；
Acetyl group；
C1-6Alkyl-carbonyl；
Amino-carbonyl；
Hydroxyl-C1-6Alkyl；
Cyano group；
Cyano group-C1-6Alkyl；
C1-6Alkoxy -C1-6Alkyl；
Carboxyl；Or
C1-6Alkoxy；
RjAnd RkEach stand alone as：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；Each RmStand alone as：
C1-6Alkyl；
Oxo；
Hydroxyl；
Amino；
C3-6Cycloalkyl；
Amino-C1-6Alkyl；
Hydroxyl-C1-6Alkyl；
Hydroxyl-C1-6Alkenyl；
C1-6Alkoxy carbonyl-C1-6Alkyl；
Halogen；
Cyano group-C1-6Alkyl；
Amino carbonyl-C1-6Alkyl；Or
C1-6Alkoxy carbonyl；
Each RnStand alone as：
C1-6Alkyl；
Oxo；
Hydroxyl；
Amino；
C3-6Cycloalkyl；
Amino-C1-6Alkyl；
Hydroxyl-C1-6Alkyl；
Hydroxyl-C1-6Alkenyl；
C1-6Alkoxy carbonyl-C1-6Alkyl；
Halogen；
Amino carbonyl-C1-6Alkyl；Or
C1-6Alkoxy carbonyl；And
RpFor hydrogen or C1-6Alkyl.
Present invention also offers the pharmaceutical composition for including the compound, method and preparation using the compound The method of the compound.
In the compound of the present invention, the group Z of Formulas I is the quaternary carbon for having heteroaryl or heterocyclyl substituent.Exceed to anticipate Material ground is compared with not having the similar compound of heteroaryl or heterocyclyl substituent on Z group, to be passed through according to the present invention straight Connect key or insertion linker and group Z at introducing heteroaryl or heterocyclic radical cause selectivity of the compound to RORc (ROR γ) Raising exceeded the raising of the selectivity to other receptor subtype RORa and RORb (ROR α and ROR β), the raising of other characteristics It is similarly such.
Definition
Unless otherwise indicated, the following term used in the application (including specification and claims) have below to The definition gone out.It must be noted that unless the context, used in specification and appended book Singulative "one" and "the" include plural form.
" alkyl " refers to monovalent straight chain or branched saturated hydrocarbon group, and it is only made up of carbon and hydrogen atom, has 1-12 carbon former Son." low alkyl group " refers to the alkyl of 1-6 carbon atom, i.e. C1-C6Alkyl.The example of alkyl includes but is not limited to methyl, second Base, propyl group, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, n-hexyl, octyl group, dodecyl etc..
" alkenyl " refers to that the linear monovalent hydrocarbon radical of the 2-6 carbon atom containing at least one double bond or 3-6 carbon are former The branched monovalent hydrocarbon group of son, such as vinyl, acrylic etc..
" alkynyl " refers to the linear monovalent hydrocarbon radical or 3-6 carbon atom of the 2-6 carbon atom containing at least one three key Branched monovalent hydrocarbon group, such as acetenyl, propinyl etc..
" alkylidene " refers to the straight chain saturation bivalent hydrocarbon radical of 1-6 carbon atom or the side chain saturation two of 3-6 carbon atom Valency alkyl, such as methylene, ethylidene, 2,2- dimethylethylenes, propylidene, 2- methyl propylenes, butylidene, pentylidene Deng.
" alkoxy " and " alkyl oxy " being interchangeable refers to formula-OR parts, and wherein R is alkane defined herein Base section.The example of alkoxy portion includes but is not limited to methoxyl group, ethyoxyl, isopropoxy etc..
" alkoxyalkyl " refers to formula Ra–O–Rb- part, wherein RaFor alkyl defined herein, RbTo be defined herein Alkylidene.Typical alkoxyalkyl includes such as 2- methoxy ethyls, 3- methoxy-propyls, 1- methyl -2- methoxyl group second Base, 1- (2- methoxy ethyls) -3- methoxy-propyls and 1- (2- methoxy ethyls) -3- methoxy-propyls.
" alkyloxy-alkoxy " refers to formula-O-R-R ' groups, and wherein R is alkylidene defined herein, and R ' is this paper institutes The alkoxy of definition.
" alkyl-carbonyl " refers to formula-C (O)-R-portion, and wherein R is alkyl defined herein.
" alkoxy carbonyl " refers to formula-C (O)-R group, and wherein R is alkoxy defined herein.
" Alkylcarbonylalkyl " refers to formula-R-C (O)-R group, and wherein R is alkylidene defined herein, and R ' is herein Defined alkyl.
" alkoxyalkylcarbonyl radicals " refer to formula-C (O)-R-R ' parts, and wherein R is alkylidene defined herein, and R ' is this Alkoxy defined in text.
" alkoxy carbonyl alkyl " refers to formula-R-C (O)-R group, and wherein R is alkylidene defined herein, and R ' is this Alkoxy defined in text.
" Alkoxycarbonylalkoxy " refers to formula-O-R-C (O)-R ' group, and wherein R is alkylidene defined herein, R ' For alkoxy defined herein.
" hydroxycarbonyl group alkoxy " refers to formula-O-R-C (O)-OH groups, and wherein R is alkylidene defined herein.
" alkyl amino-carbonyl alkoxy " refers to formula-O-R-C (O)-NHR ' groups, and wherein R is alkylene defined herein Base, R ' are alkyl defined herein.
" dialkyl amino carbonyl alkoxy " refers to formula-O-R-C (O)-NR ' R " groups, and wherein R is Asia defined herein Alkyl, R ' and R " are alkyl defined herein.
" alkylaminoalkoxy " refers to formula-O-R-NHR ' groups, and wherein R is alkylidene defined herein, and R ' is this Alkyl defined in text.
" dialkylaminoalkoxy groups " refer to formula-O-R-NR ' R ' groups, and wherein R is alkylidene defined herein, R ' and R " is alkyl defined herein.
" alkyl sulphonyl " refers to formula-SO2- R-portion, wherein R are alkyl defined herein.
" Alkylsulfonylalkyl " refers to formula-R'-SO2- R " parts, wherein R ' are alkylidene defined herein, and R " is Alkyl defined herein.
" alkyl sulphonyl alkoxy " refers to formula-O-R-SO2- R ' group, wherein R are alkylidene defined herein, R ' For alkyl defined herein.
" amino " refers to formula-NRR' parts, and wherein R and R ' each stand alone as hydrogen or alkyl defined herein.Therefore " ammonia Base " includes " alkyl amino " (wherein one of R and R ' are alkyl, and another is hydrogen) and " dialkyl amido ", and (wherein R and R ' are Alkyl).
" amino carbonyl " refers to formula-C (O)-R group, and wherein R is amino defined herein.
" N- hydroxy-aminos carbonyl " refers to formula-C (O)-NR-OH groups, and wherein R is hydrogen or alkyl defined herein.
" N- alkoxies-amino carbonyl " refers to formula-C (O)-NR-R ' groups, and wherein R is hydrogen or alkyl, and R ' is determined by this paper The alkoxy of justice.
" N- alkyl-aminocarbonyls " refers to formula-C (O)-NH-R groups, and wherein R is alkyl defined herein.
" N- hydroxy-ns-alkyl amino-carbonyl " refers to formula-C (O)-NRR ' groups, and wherein R is alkyl defined herein, R ' is hydroxyl.
" N- alkoxy-N- alkyl amino-carbonyls " refers to formula-C (O)-NRR ' groups, and wherein R is alkane defined herein Base, R ' are alkoxy defined herein.
"-the C of N, N- bis-1-6Alkyl-aminocarbonyl " refers to formula-C (O)-NRR ' groups, and wherein R and R ' are defined herein Alkyl.
" amino-sulfonyl " refers to formula-SO2-NH2Group.
" N- alkyl amino sulfonyls " refers to formula-SO2- NHR groups, wherein R are alkyl defined herein.
" N, N- dialkyl amino sulfonyl " refers to formula-SO2- NRR ' groups, wherein R and R ' are alkane defined herein Base.
" alkyl sulfonyl-amino " refers to formula-NR '-SO2- R group, wherein R are alkyl, and R ' is hydrogen or defined herein Alkyl.
" N- (alkyl sulphonyl)-aminoalkyl " refers to formula-R-NH-SO2- R ' group, wherein R are Asia defined herein Alkyl, R ' are alkyl defined herein.
" N- (alkyl sulphonyl) amino carbonyl " refers to formula-C (O)-NH-SO2- R group, wherein R are defined herein Alkyl.
" N- (alkyl sulphonyl)-N- alkyl amino-carbonyls " refers to formula-C (O)-NR-SO2- R ' group, wherein R and R ' are Alkyl defined herein.
" N- alkoxyalkyls-amino carbonyl " refers to formula-C (O)-NR-R '-OR " group, wherein R is hydrogen or alkyl, and R ' is Alkylidene, R " are alkyl defined herein.
" N- hydroxyalkyl-aminos carbonyl " refers to formula-C (O)-NR-R '-OH " group, wherein R is hydrogen or alkyl, and R ' is this Alkylidene defined in text.
" alkoxy amino " refers to formula-NR-OR' parts, and wherein R is hydrogen or alkyl, and R' is alkyl defined herein.
" alkyl alkylthio base " refers to formula-SR parts, and wherein R is alkyl defined herein.
" aminoalkyl " refers to that group-R-R', wherein R' are amino, and R is alkylidene defined herein.
" aminoalkyl " includes amino methyl, amino-ethyl, 1- aminopropyls, 2- aminopropyls etc.." aminoalkyl " Amino part can be substituted once or secondary to obtain " alkylaminoalkyl group " and " dialkyl aminoalkyl " respectively by alkyl. " alkylaminoalkyl group " includes Methylaminomethyl, methylaminoethyl, dimethylaminopropyl, ethylaminoethyl etc.." dioxane Base aminoalkyl " includes dimethylaminomethyl, dimethyl aminoethyl, dimethylaminopropyl, N- methyl-N-ethylaminos Ethyl etc..
" aminoalkoxy " refers to that group-OR-R', wherein R' are amino, and R is alkylidene defined herein.
" alkyl sulphonyl acylamino- " refers to formula-NR'SO2- R-portion, wherein R are alkyl, and R' is hydrogen or alkyl.
" amino carbonyl epoxide alkyl " or " carbamoylalkyl " refer to formula-R-O-C (O)-NR'R " groups, and wherein R is Alkylidene, R' and R " each stand alone as hydrogen or alkyl defined herein.
" alkynyl alkoxy " refers to formula-O-R-R' groups, and wherein R is alkylidene, and R' is alkynyl defined herein.
" aryl " refers to the monovalent cyclic aromatic moiety being made up of monocyclic, bicyclic or tricyclic aromatic ring.Aryl can be such as this It is optionally substituted defined in text.The example of aryl moiety includes but is not limited to phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, ring penta Dialkylene, Ao Ji, epoxide diphenyl, xenyl, methylenediphenyl, aminodiphenyl base, diphenylsulfidyl (sulfidyl), two Dioxa between phenyl sulfonyl, diphenyl isopropyl subunit (propylidenyl), benzodioxan base, benzofuranyl, benzo Cyclopentenyl, benzopyranyl, benzoxazinyl, benzoxazine ketone group, benzo piperidyl, benzo piperazinyl, benzopyrrole alkane Base, benzo morpholinyl, methylenedioxyphenyl base, ethylenedioxyphenyl etc., they can be optional as herein defined It is substituted.
" aryl alkyl " and " aralkyl " is interchangeable, and refers to group-RaRb, wherein RaFor alkylidene, RbFor herein Defined aryl；For example, the example of aryl alkyl is phenylalkyl, such as benzyl, phenylethyl, 3- (3- chlorophenyls)- 2- methyl amyls etc..
" aryl sulfonyl " refers to formula-SO2- R group, wherein R are aryl defined herein.
" aryloxy " refers to formula-O-R groups, and wherein R is aryl defined herein.
" aralkyl oxy " refers to formula-O-R-R " groups, and wherein R is alkylidene, and R' is aryl defined herein.
" carboxyl " or " hydroxycarbonyl group " is interchangeable, and refers to formula-C (O)-OH groups.
" cyanoalkyl " refers to formula-R '-R " part, wherein R ' is alkylidene defined herein, and R " is cyano group or nitrile.
" cycloalkyl " refers to by the monocyclic or bicyclic monovalent saturated carbon ring part formed.Special cycloalkyl is unsubstituted Or substituted by alkyl.Cycloalkyl optionally can be substituted as defined herein.Unless otherwise defined, cycloalkyl can optional quilt One or more substituents substitute, wherein each substituent stands alone as hydroxyl, alkyl, alkoxy, halogen, haloalkyl, amino, list Alkyl amino or dialkyl amido.The example of cycloalkyl moiety include but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Suberyl etc., including unsaturated (cycloalkenyl group) derivative in its part.
" cycloalkenyl group " refers to the cycloalkyl defined herein comprising at least one double bond or degree of unsaturation.Typical cyclenes Base includes cyclohexenyl group, cyclopentenyl, cyclobutane base etc..
" cycloalkyl-alkyl " refers to formula-R '-R " part, wherein R ' is alkylidene, and R " is cycloalkyl defined herein.
" cycloalkyl alkoxy " refers to formula-O-R-R ' groups, and wherein R is alkylidene, and R ' is cycloalkyl defined herein.
" naphthene base carbonyl " refers to formula-C (O)-R-portion, and wherein R is cycloalkyl defined herein.
“C3-6Cycloalkyl-C1-6Alkyl-carbonyl " refers to that formula-C (O)-R, wherein R are cycloalkyl-alkyl defined herein.
" cyanoalkyl carbonyl " refers to formula-C (O)-R-R ' parts, and wherein R is alkylidene defined herein, and R ' is cyano group Or nitrile.
" N- cyano group-amino carbonyl " refers to formula-C (O)-NHR parts, and wherein R is cyano group or nitrile.
" N- cyano group-N- alkyl-aminocarbonyls " refers to formula-C (O)-NRR '-R-portion, and wherein R ' is alkane defined herein Base, R are cyano group or nitrile.
" naphthene sulfamide base " refers to formula-SO2- R group, wherein R are cycloalkyl defined herein.
" cycloalkyl-alkyl sulfonyl " refers to formula-SO2- R group, wherein R are cycloalkyl-alkyl defined herein.
" formoxyl " refers to formula-C (O)-H parts.
" heteroaryl " refers to the monocyclic or bicyclic radicals of the 5-12 annular atom with least one aromatic ring, the virtue Race's ring includes 1,2 or 3 ring hetero atom for being selected from N, O or S, and remaining annular atom is C, it will be understood that the tie point of heteroaryl On aromatic ring.Heteroaryl ring can be optionally substituted as defined herein.The example of heteroaryl moieties is included but not It is limited to imidazole radicals, oxazolyl, isoxazolyls, thiazolyl, isothiazolyl, oxadiazolyls, thiadiazolyl group, the pyrazine optionally substituted Base, thienyl, benzothienyl, thienyl, furyl, pyranose, pyridine radicals, pyrrole radicals, pyrazolyl, pyrimidine radicals, quinolyl, Isoquinolyl, benzofuranyl, benzothienyl, benzothiopyran derivative base, benzimidazolyl, benzoxazolyl, Ben Bing oxadiazolyl, It is benzothiazolyl, diazosulfide base, benzopyranyl, indyl, isoindolyl, triazolyl, triazine radical, quinoxalinyl, fast Purine base, quinazolyl, quinolizine base, 1,5- phthalazinyls, pteridyl, carbazyl, azepineBase, diazaBase, acridinyl Deng each of which can be optionally substituted as defined herein.
" heteroaryl alkyl " or " heteroarylalkyl " refers to formula-R-R' groups, and wherein R is alkylidene, and R' is defined herein Heteroaryl.
" heteroarylsulfonyl " refers to formula-SO2- R group, wherein R are heteroaryl defined herein.
" heteroaryl epoxide " refers to formula-O-R groups, and wherein R is heteroaryl defined herein.
" heteroarylalkyl epoxide " refers to formula-O-R-R " groups, and wherein R is alkylidene, and R' is heteroaryl defined herein.
Term " halo ", " halogen " and " halide " is interchangeable, and refers to substituent fluorine, chlorine, bromine or iodine.
" haloalkyl " refers to alkyl defined herein, and wherein one or more hydrogen are taken by identical or different halogen Generation.Typical haloalkyl includes-CH2Cl、–CH2CF3、–CH2CCl3, perfluoroalkyl (such as-CF3) etc..
" halogenated alkoxy " refers to formula-OR parts, and wherein R is haloalkyl defined herein.Typical haloalkoxy Base is difluoro-methoxy.
" heterocyclic amino group " refers to that wherein at least one annular atom forms Asia for N, NH or N- alkyl and remaining annular atom The ring of the saturation of alkyl.
" heterocyclic radical " refer to its by 1-3 ring group into monovalent saturation part, it mixes (the choosing of 1,2 or 3 or 4 hetero atom From nitrogen, oxygen or sulphur).The heterocyclic ring can be optionally substituted as defined herein.The example of heterocyclyl moieties is included but not It is limited to piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, the azepine optionally substitutedBase, pyrrolidinyl, azetidinyl, THP trtrahydropyranyl, tetrahydrofuran base, oxetanyl etc..Such heterocyclic radical can optionally be taken as defined herein Generation.
" cycloheteroalkylalkyl " refers to formula-R-R' groups, and wherein R is alkylidene defined herein, and R' is defined herein Heterocyclic radical.
" heterocyclic radical epoxide " refers to formula-OR parts, and wherein R is heterocyclic radical defined herein.
" heterocyclylalkoxy " refers to formula-OR-R' parts, and wherein R is alkylidene defined herein, and R' is determined by this paper The heterocyclic radical of justice.
" hydroxy alkoxy base " refers to formula-OR parts, and wherein R is hydroxy alkyl defined herein.
" hydroxyalkylamino " refers to formula-NR-R' parts, and wherein R is hydrogen or alkyl, and R' is hydroxyl alkane defined herein Base.
" hydroxyalkylaminoalkyl " refers to formula-R-NR'-R " parts, and wherein R is alkylidene, and R' is hydrogen or alkyl, and R " is Hydroxy alkyl defined herein.
" hydroxycarbonylalkyl " or " carboxyalkyl " refers to formula-R- (CO)-OH groups, and wherein R is Asia defined herein Alkyl.
" hydroxycarbonyl group alkoxy " refers to formula-O-R-C (O)-OH groups, and wherein R is alkylidene defined herein.
" hydroxyalkylcarbonyl " refers to formula-C (O)-R-R ' parts, and wherein R is alkylidene defined herein, and R ' is hydroxyl Base.
" hydroxy alkyl Epoxide carbonyl alkyl " or " hydroxy alkoxy base carbonylic alkyl " refers to formula-R-C (O)-O-R-OH groups, Wherein each R is alkylidene, can be identical and different.
" hydroxy alkyl " refers to alkyl defined herein, is substituted by one or more (such as 1,2 or 3) hydroxyls, premise It is that identical carbon atom does not carry more than one hydroxyl.Representational example includes but is not limited to hydroxymethyl, 2- hydroxyl second Base, 2- hydroxypropyls, 3- hydroxypropyls, 1- (hydroxymethyl) -2- methyl-propyls, 2- hydroxybutyls, 3- hydroxybutyls, 4- hydroxyls Butyl, 2,3- dihydroxypropyls, 2- hydroxyl -1- hydroxymethylethyls, 2,3- dihydroxy butyl, 3,4- dihydroxy butyl and 2- (hydroxymethyl) -3- hydroxypropyls.
" hydroxycycloalkyl " refers to cycloalkyl defined herein, and 1,2 or 3 hydrogen atom wherein in cycloalkyl is by hydroxyl Substituent substitutes.Representational example includes but is not limited to 2-, 3- or 4- hydroxy-cyclohexyl etc..
" oxo " refers to formula=O (oxygen for carrying double bond) part.Therefore 1- oxo-ethyls are acetyl group.
" alkoxy hydroxy alkyl " and " hydroxy alkoxy alkyl " are interchangeable, and refer to alkane as herein defined Base, it is optionally substituted by a hydroxyl group at least once, substituted at least once by alkoxy.
" alkoxy hydroxy alkyl " and " hydroxy alkoxy alkyl " therefore including such as 2- hydroxy-3-methoxies -propyl- 1- bases Deng.
" urea " or " urea groups " refers to formula-NR'-C (O)-NR " R " groups, wherein each standing alone as hydrogen or alkyl.
" carbamate " refers to formula-O-C (O)-NR'R " group, wherein R' and R " each stands alone as hydrogen or alkyl.
" carboxyl " refers to formula-O-C (O)-OH groups.
" sulfonamido " refers to formula-SO2- NR'R " groups, wherein R', R " and R " ' each stand alone as hydrogen or alkyl.
When being partly applied in combination with " aryl ", " phenyl ", " heteroaryl ", " cycloalkyl " or " heterocyclic radical ", " optionally substitution " refer to that such part can be unsubstituted (that is, all open valence links are occupied by hydrogen atom) or can be described herein Special groups substitution.
" leaving group " refers to the group in synthetic organic chemistry with relative conventional sense, i.e., anti-in substitution Replaceable atom or group under the conditions of answering.The example of leaving group includes but is not limited to halogen, alkane-or arlydene sulfonyl Epoxide, such as mesyl epoxide, ethylsulfonyl epoxide, sulphomethyl, benzenesulfonyl epoxide, tosyl epoxide and thiophene Base epoxide, dihalo phosphino- epoxide (phosphinoyloxy), optionally substituted benzyl epoxide, isopropoxy, acyloxy etc..
" conditioning agent " refers to the molecule with target spot interaction.The interaction is including but not limited to as herein defined Activator, antagonist etc..
" optional " or " optional " refers to that the event then described or situation may occur but be not necessarily to occur, the description bag Include the situation that the situation of wherein event or situation generation and event or situation do not occur.
" disease " and " morbid state " refers to any disease, illness, symptom, imbalance or indication.
" inert organic solvents " or " atent solvent " refer to that solvent is inert under the reaction condition of description associated therewith, Including such as benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, METHYLENE CHLORIDE or dichloromethane, ether, Ethyl acetate, acetone, MEK, methanol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, dioxane, pyridine etc..Unless there are opposite Regulation, the solvent that uses is atent solvent in present invention reaction.
" pharmaceutically useful " refer to can be used for prepare Pharmaceutical composition, it is typically safe and nontoxic and biologically or its Its aspect be it is desirable, including animal doctor and human medicine use it is acceptable.
" the pharmaceutically useful salt " of compound refers to pharmaceutically useful salt defined herein, and it has needed for parent compound Pharmacological activity.
It should be appreciated that the as herein defined molten of identical acid-addition salts is included to all references of pharmaceutically useful salt Agent addition form (solvate) or crystalline form (polymorph).
" blocking group " is the group for referring to optionally block a reaction site in polyfunctional compound, so as to Enable to another unprotected reaction site that chemical reaction can be in synthesis chemistry on relative conventional meaning Place is optionally carried out.Some methods of the present invention depend on active nitrogen and/or oxygen present in blocking group blocking reaction thing. For example, term " amino protecting group " and " nitrogen-protecting group group " are used interchangeably herein, refer to be intended to protect in building-up process Shield nitrogen-atoms avoids those organic groups of undesirable reaction.Typical nitrogen-protecting group group includes but is not limited to trifluoroacetyl Base, acetylamino, benzyl (Bn), benzyloxycarbonyl (carbonylbenzyloxy, CBZ), to methoxybenzyloxycarbonyl, to nitro benzyloxy Base carbonyl, tert-butoxycarbonyl (BOC) etc..Skilled person will know how selection, one is easy to remove and has and can hold By the group of the ability of following reaction.
" solvate " refers to the solvent addition form containing stoichiometry or non-stoichiometric solvent.Some compounds Tend to capture the solvent molecule of the fixed molar ratio under crystalline solid state, so as to form solvate.If solvent is water, The solvate then formed is hydrate, and when solvent is alcohol, the solvate of formation is alcoholates.Hydrate be by one or It is H that multiple hydrones can keep it with its reclaimed water2The combination of one of O material of molecular state is formed, and such combination can Form one or more hydrates.
" arthritis " refer to can result in body joints damage and the pain related to such joint injury disease or Illness.Arthritis include rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathy, Urarthritis, systemic loupus erythematosus and juvenile arthritis, osteoarthritis and other arhritis conditions.
" respiratory disease " refers to but is not limited to chronic obstructive pulmonary disease (COPD), asthma, bronchial spasm etc..
" individual " refers to mammal and nonmammalian.Mammal refers to any member of mammal, including But it is not limited to the mankind；Inhuman primate, such as chimpanzee and other apes and monkey kind；Farm-animals, such as ox, horse, silk floss Sheep, goat and pig；Domestic animal, such as rabbit, dog and cat；Laboratory animal, including rodent, such as rat, mouse and cavy Deng.The example of nonmammalian includes but is not limited to birds etc..Term " individual " does not indicate that specific age or sex.
" therapeutically effective amount " refers to sufficiently achieve such treatment morbid state when being administered to treat morbid state to individual Compound amount." therapeutically effective amount " depends on the compound, morbid state to be treated, the serious journey of disease to be treated Degree, the age of individual and relative health, the approach and form of administration, the factor such as judgement of attending doctor or veterinarian.
When being related to variable, term " defined above those " and " those defined herein " are as reference variable Generalized definition and specific definition are hereby incorporated (if any).
" treatment " of morbid state includes, and particularly suppresses morbid state, that is, prevents morbid state or its clinical symptoms Development, and/or alleviate morbid state, that is, morbid state or its clinical symptoms are temporarily or permanently disappeared.
When referring to a chemical reaction, term " processing ", " contact " and " reaction " refers to add or mix under suitable condition Product that close two or more reagents to produce requirement and/or desired.Require and/or it is expected it should be understood that producing Product reactions vary fixed is directly produced by the combination for two kinds of reagents being initially added, it is possible to be may eventually lead to the formation of will Ask and/or the mixture of desired product in caused one or more intermediates.
Nomenclature and structure
In general, the nomenclature and chemical name that use in this application are to be based on CambridgeSoftTM's ChembioOfficeTM.Unless otherwise indicated, any open chemical combination on carbon, oxygen, sulphur or nitrogen-atoms is appeared in this paper structures Valency represents hydrogen atom be present.When nitrogenous heteroaryl ring is being shown on nitrogen-atoms with open valency, and shown on heteroaryl ring Variable such as Ra、RbOr RcWhen, these variables can be combined or connected with the nitrogen of open valency.When exist in structure chiral centre but When chiral centre does not show specific spatial chemistry, related to chiral centre two kinds of enantiomers are all contained in the structure.When In the presence of structure shown in this article is with a variety of tautomeric forms, all such dynamic isomers are included in the structure. The atom represented in this paper structures is intended to all naturally occurring isotopes of such atom.Thus, for example, table herein The hydrogen atom shown should include deuterium and tritium, and carbon atom should include C13And C14Isotope.One or more carbon of the compounds of this invention Atom can be substituted by one or more silicon atoms, it is contemplated that one or more oxygen of the compounds of this invention can be replaced by sulphur or selenium atom Generation.
The compounds of this invention
The invention provides compound of formula I or its pharmaceutically useful salt：
Wherein：
M is 0 or 1；
N is 0 or 1；
P is 0-3；
Q is 0,1 or 2；
R is f1,2 or 3；
A is：
Key；
-(CRjRk)t-；
-C(O)-(CRjRk)t-；
-(CRjRk)t-C(O)-；
-NRa-(CRjRk)t-；
-(CRjRk)t-NRa-；
-C(O)NRa-(CRjRk)t-；
-(CRjRk)t-NRaC(O)-；
-O-(CRjRk)t-；
-(CRjRk)t-O-；
-S-(CRjRk)t-；
-(CRjRk)t-S-；
-SO2-(CRjRk)t-；
-(CRjRk)t-SO2-；Or
T is 0-4；
W is：
-CRbRc-；
-O-；
-S-；
-SO2-；Or
-NRd-；
X1、X2、X3And X4One of be N, remaining is CRe；
Or X1、X2、X3And X4In two be N, remaining is CRe；
Or X1、X2、X3And X4In three be N, another is CRe；
Or X1、X2、X3And X4It is CRe；
Y is：
-O-；
-S-；
-SO2-；
-CRfRg-；Or
-NRh-；
Z is：
Key；
-C1-6Alkylidene-；
-NRp-C1-6Alkylidene；
-C1-6Alkylidene-NRp-；
-NRp-；
-C(O)-；
-C(O)NRp-；
-C(O)NRp-C1-6Alkylidene；
-NRpC(O)-；
-NRpC(O)-C1-6Alkylidene；
-C1-6Alkylidene-O-；
-O-C1-6Alkylidene-；Or
-C1-6Alkylidene-O-C1-6Alkylidene-；
Het is：
Heteroaryl, it is selected from：
Oxazolyl；
Isoxazolyl；
Thiazolyl；
Isothiazolyl；
Pyrazolyl；
Triazolyl；
Oxadiazolyl；
Thiadiazolyl group；
Pyridine radicals；
Pyrimidine radicals；
Pyrazinyl；Or
Imidazole radicals；
Wherein each heteroaryl can be unsubstituted or by RmSubstitution is one or more times；Or
Heterocyclic radical, it is selected from：
Oxetanylmethoxy；
Tetrahydrofuran base；
THP trtrahydropyranyl；
Pyrrolidinyl；
Piperidyl；
Piperazinyl；
Oxazole alkyl；
Imidazolidinyl；
Morpholinyl；
Thio-morpholinyl；Or
1,1- dioxothiomorpholinyls；
Wherein each heterocyclic radical can be unsubstituted or by RnSubstitution is one or more times；
R1、R2、R3、R4、R5、R6、R7And R8Each stand alone as：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Or R3And R4Ethylidene is formed together with the atom connected with them；
Or R3And R4It can be formed together with the atom connected with them 3,4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R5And R6It can be formed together with the atom connected with them 3,4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R7And R8It can be formed together with the atom connected with them 3,4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R3And R4One of and R5And R6One of and their atoms for being connected can be formed together 3,4,5,6 or 7 yuan it is full Sum or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optional By RiSubstitution is one or more times；
Or R5And R6One of and R7And R8One of and their atoms for being connected can be formed together 3,4,5,6 or 7 yuan it is full Sum or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optional By RiSubstitution is one or more times；
Each R9Stand alone as：
C1-6Alkyl；
Halogen；
C1-6Alkoxy；Or
Cyano group；
Wherein C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；
R10For：
Hydrogen；
Carboxyl；
C1-6Alkyl-carbonyl；
C1-6Alkoxy-carbonyl；
Oxo；
Hydroxyl；
Amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Cyano group；
Hydroxyl-C1-6Alkyl；
N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl；
N- hydroxyls-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-amino carbonyl；
Halogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times or oxo；
R11For：
Hydrogen；
Halogen；
Carboxyl；
C1-6Alkyl-carbonyl；
C1-6Alkoxy-carbonyl；
Oxo；
Hydroxyl；
Amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
C1-6Alkyl-sulfonylamino；
C1-6Alkyl-sulfonylamino-C1-6Alkyl；
Cyano group；
Hydroxyl-C1-6Alkyl；
N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl；
N- hydroxyls-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-amino carbonyl；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times or oxo；
Or R10And R11It can be formed together with the atom connected with them 3,4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R10And R11Double bond is formed together with the atom connected with them；
R12For：
Hydrogen；
Halogen；
Carboxyl；
C1-6Alkyl-carbonyl；
C1-6Alkoxy-carbonyl；
Oxo；
Hydroxyl；
Amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Cyano group；
Hydroxyl-C1-6Alkyl；
N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl；
N- hydroxyls-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-amino carbonyl；Or
C1-6Alkyl, it can be unsubstituted or be substituted one or more times by halogen or oxo；
R13For：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Ra、Rb、RcAnd RdEach stand alone as：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Or RbAnd RcIt can be formed together with the atom connected with them 3,4,5,6 or 7 yuan of saturations or fractional saturation Ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or RbAnd RcOne of and R7And R8One of and their atoms for being connected can be formed together 3,4,5,6 or 7 yuan it is full Sum or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optional By RiSubstitution is one or more times；
Or RbAnd RcOne of and R5And R6One of and their atoms for being connected can be formed together 3,4,5,6 or 7 yuan it is full Sum or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optional By RiSubstitution is one or more times；
Each ReStand alone as：
Hydrogen；
C1-6Alkyl；
Halogen；
C1-6Alkoxy；Or
Cyano group；
Wherein C1-6Moieties can be unsubstituted or by halogen, hydroxyl or C1-6Alkoxy substitutes one or more times；
RfFor：
Hydrogen；
Halogen；
C1-6Alkoxy；Or
C1-6Alkyl, it can be unsubstituted or by halogen, hydroxyl or C1-6Alkoxy substitutes one or more times；
RgFor：
Hydrogen；
C1-6Alkyl；
C3-6Cycloalkyl, it can be unsubstituted or by C1-6Alkyl substitution is once or secondary；
C2-6Alkenyl；
C3-6Cycloalkenyl group；
C3-6Cycloalkyl-C1-6Alkyl；
Halogen；
C1-6Alkyl-carbonyl；
C3-6Cycloalkyl-carbonyl；
C3-6Cycloalkyl-C1-6Alkyl-carbonyl；
Cyano group-C1-6Alkyl-carbonyl；
Hydroxyl-C1-6Alkyl-carbonyl；
C1-6Alkoxy -C1-6Alkyl-carbonyl；
Carboxyl；
N- cyano group-amino carbonyl；
N- cyano group-N-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkyl-ethanamidine base；
N, N '-two-C1-6Alkyl-ethanamidine base；
N '-cyano group-N-C1-6Alkyl-ethanamidine base；
N'- hydroxy-acetamidine bases；
N'-C1-6Alkoxy-ethanamidine base；
N'- hydroxy-ns-C1-6Alkyl-ethanamidine base；
N'-C1-6Alkoxy-N-C1-6Alkyl-ethanamidine base；
2- nitros -1-N-C1-6Alkyl amino-vinyl；Formoxyl；
C1-6Alkyl-sulfonyl base；
C3-6Cycloalkyl-sulfonyl；
C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；
C1-6Alkyl-sulfonyl base-C1-6Alkyl；
Amino carbonyl；
Carbonylamino；
N- hydroxy-amino carbonyls；
N-C1-6Alkoxy-amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
Amino carbonyl-C1-6Alkyl；
N-C1-6Alkyl-aminocarbonyl-C1-6Alkyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl-C1-6Alkyl；
C1-6Alkoxy-carbonyl；
N- hydroxy-ns-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Amino-sulfonyl；
N-C1-6Alkyl-amino sulfonyl；
- the C of N, N- bis-1-6Alkyl-amino sulfonyl；
Cyano group；
C1-6Alkoxy；
C1-6Alkyl-sulfonylamino；
N-C1-6Alkyl-sulfonylamino carbonyl；
N-(C1-6Alkyl-sulfonyl base)-N-C1-6Alkyl-aminocarbonyl；
N-(C1-6Alkyl-sulfonyl base)-amino-C1-6Alkyl；Amino；
N-C1-6Alkyl-amino；
- the C of N, N- bis-1-6Alkyl-amino；
Halo-C1-6Alkyl；
Phenyl；
Heterocyclic radical；
Heteroaryl；
C1-6Alkyl-carbonylamino；
Carbonylamino；Or
Hydroxyl；
Wherein C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；
And
Wherein phenyl, heterocyclic radical, heteroaryl, C3-6Cycloalkyl, C3-6Cycloalkenyl group and C3-6Cycloalkyl-C1-6Moieties can be with It is unsubstituted or by RiSubstitution is one or more times；
Or RfAnd RgOxo can be formed together；
Or RfAnd Rg4,5,6 or 7 yuan of saturations or fractional saturation ring can be formed together with the atom connected with them, It optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
RhFor：
Hydrogen；
C1-6Alkyl；
C3-6Cycloalkyl；
C3-6Cycloalkenyl group；
C3-6Cycloalkyl-C1-6Alkyl；
C1-6Alkyl-carbonyl；
C3-6Cycloalkyl-carbonyl；
C3-6Cycloalkyl-C1-6Alkyl-carbonyl；
Cyano group-C1-6Alkyl-carbonyl；
Hydroxyl-C1-6Alkyl-carbonyl；
C1-6Alkoxy -C1-6Alkyl-carbonyl；
N- cyano group-amino carbonyl；
N- cyano group-N-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkyl-ethanamidine base；
N, N '-two-C1-6Alkyl-ethanamidine base；
N '-cyano group-N-C1-6Alkyl-ethanamidine base；
N'- hydroxy-acetamidine bases；
N'-C1-6Alkoxy-ethanamidine base；
N'- hydroxy-ns-C1-6Alkyl-ethanamidine base；
N'-C1-6Alkoxy-N-C1-6Alkyl-ethanamidine base；
2- nitros -1-N-C1-6Alkyl amino-vinyl；
Formoxyl；
C1-6Alkyl-sulfonyl base；
C3-6Cycloalkyl-sulfonyl；
C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；
C1-6Alkyl-sulfonyl base-C1-6Alkyl；
Amino carbonyl；
N- hydroxy-amino carbonyls；
N-C1-6Alkoxy-amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
N- hydroxy-ns-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Amino-sulfonyl；
N-C1-6Alkyl-amino sulfonyl；
- the C of N, N- bis-1-6Alkyl-amino sulfonyl；
Cyano group；
C1-6Alkyl-sulfonylamino；
C1-6Alkyl-sulfonylamino-C1-6Alkyl；
N-(C1-6Alkyl-sulfonyl base) amino carbonyl；
N-(C1-6Alkyl-sulfonyl base)-N-C1-6Alkyl-aminocarbonyl；
N-(C1-6Alkyl-sulfonyl base)-amino-C1-6Alkyl；
Amino carbonyl-C1-6Alkyl；
N-C1-6Alkyl-aminocarbonyl-C1-6Alkyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl-C1-6Alkyl；
C1-6Alkoxy-carbonyl；
Phenyl；
Heterocyclic radical；Or
Heteroaryl；
Wherein C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；With
Wherein phenyl, heterocyclic radical, heteroaryl, C3-6Cycloalkyl, C3-6Cycloalkenyl group and C3-6Cycloalkyl-C1-6Moieties can be with It is unsubstituted or by RiSubstitution is one or more times；
Or RhAnd R10And R11One of can be formed together with the atom that they are connected 4,5,6 or 7 yuan of aromatics, saturation or The ring of fractional saturation, it optionally can be selected from other-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by Ri Substitution is one or more times；
Or RfAnd RgOne of and R10And R11One of and their atoms for being connected can form 3,4,5,6 or 7 yuan together Aromatics, saturation or fractional saturation ring, it optionally can be selected from other-O- ,-NR comprising 1 or 2a- or-S- hetero atom, It can be optionally by RiSubstitution is one or more times；
RiFor：
C1-6Alkyl；
Halo-C1-6Alkyl；
C3-6Cycloalkyl；
Halogen；
Oxo；
Hydroxyl；
Acetyl group；
C1-6Alkyl-carbonyl；
Amino-carbonyl；
Hydroxyl-C1-6Alkyl；
Cyano group；
Cyano group-C1-6Alkyl；
C1-6Alkoxy -C1-6Alkyl；
Carboxyl；Or
C1-6Alkoxy；
RjAnd RkEach stand alone as：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Each RmStand alone as：
C1-6Alkyl；
Oxo；
Hydroxyl；
Amino；
C3-6Cycloalkyl；
Amino-C1-6Alkyl；
Hydroxyl-C1-6Alkyl；
Hydroxyl-C1-6Alkenyl；
C1-6Alkoxy carbonyl-C1-6Alkyl；
Halogen；
Cyano group-C1-6Alkyl；
Amino carbonyl-C1-6Alkyl；Or
C1-6Alkoxy carbonyl；
Each RnStand alone as：
C1-6Alkyl；
Oxo；
Hydroxyl；
Amino；
C3-6Cycloalkyl；
Amino-C1-6Alkyl；
Hydroxyl-C1-6Alkyl；
Hydroxyl-C1-6Alkenyl；
C1-6Alkoxy carbonyl-C1-6Alkyl；
Halogen；
Amino carbonyl-C1-6Alkyl；Or
C1-6Alkoxy carbonyl；And
RpFor：
Hydrogen；Or
C1-6Alkyl.
In some embodiments of Formulas I, m 0.
In some embodiments of Formulas I, m 1.
In some embodiments of Formulas I, n 0.
In some embodiments of Formulas I, n 1.
In some embodiments of Formulas I, p 0-2.
In some embodiments of Formulas I, p is 0 or 1.
In some embodiments of Formulas I, p 0.
In some embodiments of Formulas I, p 1.
In some embodiments of Formulas I, p 2.
In some embodiments of Formulas I, p 3.
In some embodiments of Formulas I, q 0.
In some embodiments of Formulas I, q 1.
In some embodiments of Formulas I, q 2.
In some embodiments of Formulas I, r 1.
In some embodiments of Formulas I, r 2.
In some embodiments of Formulas I, r 3.
In some embodiments of Formulas I, t 0-3.
In some embodiments of Formulas I, t 0.
In some embodiments of Formulas I, t 1.
In some embodiments of Formulas I, t 2.
In some embodiments of Formulas I, t 3.
In some embodiments of Formulas I, A is：Key；-CH2-；-C(O)-；-NRa-；-O-；-S-；Or-SO2-。
In some embodiments of Formulas I, A is：Key；-(CRjRk)t-；-C(O)-(CRjRk)t-；-(CRjRk)t-C (O)-；-(CRjRk)t-NRa-；-C(O)NRa-(CRjRk)t-；-(CRjRk)t-NRaC(O)-；-(CRjRk)t-O-；-(CRjRk)t- S-；Or-(CRjRk)t-SO2-。
In some embodiments of Formulas I, A is：Key；-C(O)-(CRjRk)t-；-(CRjRk)t-C(O)-；-(CRjRk)t- NRa-；-C(O)NRa-(CRjRk)t-；(CRjRk)t-NRaC(O)-；Or-(CRjRk)t-O-。
In some embodiments of Formulas I, A is：Key；-NRa-；-O-；Or-S-.
In some embodiments of Formulas I, A is：Key；-NRa-；Or-O-.
In some embodiments of Formulas I, A is：Key；Or-(CRjRk)t-O-。
In some embodiments of Formulas I, A is key.
In some embodiments of Formulas I, A is-CH2-。
In some embodiments of Formulas I, A be-C (O)-.
In some embodiments of Formulas I, A is-NRa-。
In some embodiments of Formulas I, A is-O-.
In some embodiments of Formulas I, A is-S-.
In some embodiments of Formulas I, A is-SO2-。
In some embodiments of Formulas I, A is-C (O) NRa-(CH2)t.
In some embodiments of Formulas I, A is-(CH2)t-NRaC(O)-。
In some embodiments of Formulas I, A is-(CRjRk)t-。
In some embodiments of Formulas I, A is-CRjRk-。
In some embodiments of Formulas I, A is-C (O)-(CRjRk)t-。
In some embodiments of Formulas I, A is-(CRjRk)t-C(O)-。
In some embodiments of Formulas I, A is-NRa-(CRjRk)t-。
In some embodiments of Formulas I, A is-(CRjRk)t-NRa-。
In some embodiments of Formulas I, A is-C (O) NRa-(CRjRk)t-。
In some embodiments of Formulas I, A is (CRjRk)t-NRaC(O)-。
In some embodiments of Formulas I, A is-O- (CRjRk)t-。
In some embodiments of Formulas I, A is-(CRjRk)t-O-。
In some embodiments of Formulas I, A is-S- (CRjRk)t-。
In some embodiments of Formulas I, A is-(CRjRk)t-S-。
In some embodiments of Formulas I, A is-SO2-(CRjRk)t-。
In some embodiments of Formulas I, A is-(CRjRk)t-SO2-。
In some embodiments of Formulas I, A is-(CH2)2-O-。
In some embodiments of Formulas I, A is-(CH2)-O-。
In some embodiments of Formulas I, A is-O- (CH2)2-。
In some embodiments of Formulas I, A is-O- (CH2)-。
In some embodiments of Formulas I, A is-(CH2)2-C(O)-。
In some embodiments of Formulas I, A is-(CH2)-C(O)-。
In some embodiments of Formulas I, A is-C (O)-(CH2)2-。
In some embodiments of Formulas I, A is-C (O)-(CH2)-。
In some embodiments of Formulas I, A is-C (O)-NH-.
In some embodiments of Formulas I, A is-CH2-C(O)-NH-。
In some embodiments of Formulas I, A is-NH-.
In some embodiments of Formulas I, A is-(CH2)2-NH-。
In some embodiments of Formulas I, A is-CH2-NH-。
In some embodiments of Formulas I, A is-NH- (CH2)2-。
In some embodiments of Formulas I, A is-NH-CH2-。
In some embodiments of Formulas I, A be-NH-C (O)-.
In some embodiments of Formulas I, t 0-3.
In some embodiments of Formulas I, t 1-3.
In some embodiments of Formulas I, t 0-2.
In some embodiments of Formulas I, t 0
In some embodiments of Formulas I, t 1.
In some embodiments of Formulas I, t 2.
In some embodiments of Formulas I, t 3.
In some embodiments of Formulas I, t 4.
In some embodiments of Formulas I, W is-CRbRc- or-O-.
In some embodiments of Formulas I, W is-CRbRc-。
In some embodiments of Formulas I, W is-O-.
In some embodiments of Formulas I, W is-NRd-。
In some embodiments of Formulas I, W is-S-.
In some embodiments of Formulas I, W is-SO2-。
In some embodiments of Formulas I, W is-CH2-。
In some embodiments of Formulas I, X1、X2、X3And X4In one or two be N, remaining is CRe。
In some embodiments of Formulas I, X1、X2、X3And X4In three be CRe, another is N.
In some embodiments of Formulas I, X1、X2、X3And X4For CRe.
In some embodiments of Formulas I, X1For N, X2、X3And X4For CRe。
In some embodiments of Formulas I, X2For N, X1、X3And X4For CRe。
In some embodiments of Formulas I, X1And X4For N, X2And X3For CRa。
In some embodiments of Formulas I, X2And X3For N, and X1And X4For CRe。
In some embodiments of Formulas I, X1And X2For N, X3And X4For CRe。
In some embodiments of Formulas I, Y is-O- ,-CRfRg- or-NRh-。
In some embodiments of Formulas I, Y is-CRfRg- or-NRh-。
In some embodiments of Formulas I, Y is-O- or-CRfRg-。
In some embodiments of Formulas I, Y is-O-.
In some embodiments of Formulas I, Y is-S-.
In some embodiments of Formulas I, Y is-SO2-。
In some embodiments of Formulas I, Y is-CRfRg-。
In some embodiments of Formulas I, Y is-NRh-。
In some embodiments of Formulas I, Z is：Key；-NRp-C1-6Alkylidene；-C(O)-；-C(O)NRp-；-C(O)NRx- C1-6Alkylidene；-NRxC(O)-；-NRx-C1-6Alkylidene；-NRx-；Or-NRxC(O)-C1-6Alkylidene.
In some embodiments of Formulas I, Z is：Key；-NRp-C1-6Alkylidene；-C(O)-；-C(O)NRp-；-NRx-C1-6 Alkylidene；Or-C (O) NRp-。
In some embodiments of Formulas I, Z is：Key；Or-NRp-C1-6Alkylidene-.
In some embodiments of Formulas I, Z is：Key；
In some embodiments of Formulas I, Z is：-C1-6Alkylidene-；
In some embodiments of Formulas I, Z is：-NRx-C1-6Alkylidene；
In some embodiments of Formulas I, Z is：-C1-6Alkylidene-NRx-；
In some embodiments of Formulas I, Z is：-NRx-；
In some embodiments of Formulas I, Z is：-C(O)-；
In some embodiments of Formulas I, Z is：-C(O)NRx-；
In some embodiments of Formulas I, Z is：-C(O)NRx-C1-6Alkylidene；
In some embodiments of Formulas I, Z is：-NRxC(O)-；
In some embodiments of Formulas I, Z is：-NRxC(O)-C1-6Alkylidene；
In some embodiments of Formulas I, Z is：-C1-6Alkylidene-O-；
In some embodiments of Formulas I, Z is：-O-C1-6Alkylidene-；Or
In some embodiments of Formulas I, Z is：-C1-6Alkylidene-O-C1-6Alkylidene-；
In some embodiments of Formulas I, Het is heteroaryl, is selected from：Oxazolyl；Isoxazolyl；Pyrazolyl；Triazolyl； Oxadiazolyl；Pyridine radicals；Pyrimidine radicals；Pyrazinyl；Or imidazole radicals；Each of which can be unsubstituted or by RmSubstitution one Or repeatedly.
In some embodiments of Formulas I, Het is heteroaryl, is selected from：Oxazolyl；Isoxazolyl；Pyrazolyl；Triazolyl； Huo oxadiazolyls；Each of which can be unsubstituted or by RmSubstitution is one or more times.
In some embodiments of Formulas I, Het Wei oxazolyls, it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het Wei isoxazolyls, it can be unsubstituted or substituted one or more It is secondary.
In some embodiments of Formulas I, Het is thiazolyl, and it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het is isothiazolyl, and it can be unsubstituted or by RmSubstitution one or Repeatedly.
In some embodiments of Formulas I, Het is pyrazolyl, and it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het is triazolyl, and it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het Wei oxadiazolyls, it can be unsubstituted or by RmSubstitution one or Repeatedly.
In some embodiments of Formulas I, Het is thiadiazolyl group, and it can be unsubstituted or by RmSubstitution one or Repeatedly.
In some embodiments of Formulas I, Het is pyridine radicals, and it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het is pyrimidine radicals, and it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het is pyrazinyl, and it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het is imidazole radicals, and it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het is oxetanylmethoxy, and it can be unsubstituted or by RmSubstitution one Or repeatedly.
In some embodiments of Formulas I, Het is tetrahydrofuran base, and it can be unsubstituted or by RmSubstitution one Or repeatedly.
In some embodiments of Formulas I, Het is THP trtrahydropyranyl, and it can be unsubstituted or by RmSubstitution one Or repeatedly.
In some embodiments of Formulas I, Het is pyrrolidinyl, and it can be unsubstituted or by RmSubstitution one or Repeatedly.
In some embodiments of Formulas I, Het is piperidyl, and it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het is piperazinyl, and it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het is oxazole alkyl, and it can be unsubstituted or by RmSubstitution one or Repeatedly.
In some embodiments of Formulas I, Het is imidazolidinyl, and it can be unsubstituted or by RmSubstitution one or Repeatedly.
In some embodiments of Formulas I, Het is morpholinyl, and it can be unsubstituted or by RmSubstitute one or more It is secondary.
In some embodiments of Formulas I, Het is thio-morpholinyl, and it can be unsubstituted or by RmSubstitution one Or repeatedly.
In some embodiments of Formulas I, Het 1,1- dioxothiomorpholinyls, its can be it is unsubstituted or By RmSubstitution is one or more times.
In some embodiments of Formulas I, Het is：3H-1,3,4- oxadiazole -2- ketone -5- bases；3- methyl isophthalic acids, 3,4- Evil Diazole -2- ketone -5- bases；4H-1,2,4- triazole -3- bases；3H-1,3,4- oxadiazole -2- ketone -5- bases；Pyrazine -2- bases；5- methyl Isoxazole -3-base；Isoxazole -3-base；The isoxazole -5-base of 3- oxos-；Oxazole -2- bases；2- methyl isophthalic acids, 2,4- triazole -3- bases； Oxazole -4- bases；1H- pyrazoles -5- bases；Pyrimidine -2-base；1H- pyrazole-3-yls；1,3,4- oxadiazole -2- carboxylate -5- bases；3- ammonia Base pyrazol-1-yl；Or N- methyl isophthalic acids, 2,4- oxadiazole -5- formamide -3- bases.
In some embodiments of Formulas I, Het 3H-1,3,4- oxadiazole -2- ketone -5- bases.
In some embodiments of Formulas I, Het is 3- methyl isophthalic acids, 3,4- oxadiazole -2- ketone -5- bases.
In some embodiments of Formulas I, Het 4H-1,2,4- triazole -3- bases.
In some embodiments of Formulas I, Het is pyrazine -2- bases.
In some embodiments of Formulas I, Het is 5- methyl-isoxazole -3- bases.
In some embodiments of Formulas I, Het Wei isoxazole -3-bases.
In some embodiments of Formulas I, Het is the isoxazole -5-base of 3- oxos-.
In some embodiments of Formulas I, Het Wei oxazole -2- bases.
In some embodiments of Formulas I, Het is 2- methyl isophthalic acids, 2,4- triazole -3- bases.
In some embodiments of Formulas I, Het Wei oxazole -4- bases.
In some embodiments of Formulas I, Het is 1H- pyrazoles -5- bases.
In some embodiments of Formulas I, Het is pyrimidine -2-base；1H- pyrazole-3-yls.
In some embodiments of Formulas I, Het 1,3,4- oxadiazole -2-cHet boxylate-5- bases.
In some embodiments of Formulas I, Het is 3- amino-pyrazol -1- bases.
In some embodiments of Formulas I, Het is N- methyl isophthalic acids, 2,4- oxadiazole -5-cHet boxamide-3- bases.
In some embodiments of Formulas I, R1For hydrogen.
In some embodiments of Formulas I, R1For C1-6Alkyl.
In some embodiments of Formulas I, R2For hydrogen.
In some embodiments of Formulas I, R2For C1-6Alkyl.
In some embodiments of Formulas I, R3For hydrogen.
In some embodiments of Formulas I, R3For C1-6Alkyl.
In some embodiments of Formulas I, R3For methyl.
In some embodiments of Formulas I, R3For halo-C1-6Alkyl.
In some embodiments of Formulas I, R3For difluoromethyl.
In some embodiments of Formulas I, R3For trifluoromethyl.
In some embodiments of Formulas I, R4For hydrogen.
In some embodiments of Formulas I, R4For C1-6Alkyl.
In some embodiments of Formulas I, R5For hydrogen.
In some embodiments of Formulas I, R5For C1-6Alkyl.
In some embodiments of Formulas I, R6For hydrogen.
In some embodiments of Formulas I, R6For C1-6Alkyl.
In some embodiments of Formulas I, R7For hydrogen.
In some embodiments of Formulas I, R7For C1-6Alkyl.
In some embodiments of Formulas I, R8For hydrogen.
In some embodiments of Formulas I, R8For C1-6Alkyl.
In some embodiments of Formulas I, R3And R43,4,5,6 or 7 yuan of saturations are formed together with the atom connected with them Or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by Ri Substitution is one or more times.
In some embodiments of Formulas I, R3And R43,4 or 5 yuan of saturations are formed together with the atom connected with them Ring.
In some embodiments of Formulas I, R5And R63,4,5,6 or 7 yuan of saturations are formed together with the atom connected with them Or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by Ri Substitution is one or more times.
In some embodiments of Formulas I, R5And R63,4 or 5 yuan of saturations are formed together with the atom connected with them Ring.
In some embodiments of Formulas I, R7And R83,4,5,6 or 7 yuan of saturations are formed together with the atom connected with them Or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by Ri Substitution is one or more times.
In some embodiments of Formulas I, R7And R83,4 or 5 yuan of saturations are formed together with the atom connected with them Ring.
In some embodiments of Formulas I, R3And R4One of and R5And R6One of and their atoms for being connected shape together Into 3,4,5,6 or 7 yuan of rings, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by Ri Substitution is one or more times.
In some embodiments of Formulas I, R5And R6One of and R7And R8One of and their atoms for being connected shape together Into 3,4,5,6 or 7 yuan of saturations or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S-'s is miscellaneous Atom, it can be optionally by RiSubstitution is one or more times.
In some embodiments of Formulas I, each R9Stand alone as：C1-6Alkyl；Halogen；Or halo-C1-6Alkyl.
In some embodiments of Formulas I, R9For C1-6Alkyl.
In some embodiments of Formulas I, R9For halogen.
In some embodiments of Formulas I, R9For C1-6Alkoxy.
In some embodiments of Formulas I, R9For cyano group.
In some embodiments of Formulas I, R9For halo-C1-6Alkyl.
In some embodiments of Formulas I, each R9Stand alone as：Fluorine；Chloro；Or trifluoromethyl.
In some embodiments of Formulas I, R10For：Hydrogen；Halogen；Or C1-6Alkyl, it can be unsubstituted or by halogen Element or oxo substitution are one or more times.
In some embodiments of Formulas I, R10For：Hydrogen or C1-6Alkyl.
In some embodiments of Formulas I, R10For hydrogen.
In some embodiments of Formulas I, R10For C1-6Alkyl.
In some embodiments of Formulas I, R10For methyl.
In some embodiments of Formulas I, R10For halogen.
In some embodiments of Formulas I, R10For carboxyl.
In some embodiments of Formulas I, R10For C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, R10For C1-6Alkoxy-carbonyl.In some embodiments of Formulas I, R10For Oxo.
In some embodiments of Formulas I, R10For hydroxyl.
In some embodiments of Formulas I, R10For amino carbonyl.
In some embodiments of Formulas I, R10For N-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, R10For the N ,-C of N- bis-1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, R10For cyano group.
In some embodiments of Formulas I, R10For hydroxyl-C1-6Alkyl.
In some embodiments of Formulas I, R10For N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, R10For N- hydroxyls-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, R10For N-C1-6Alkoxy-amino carbonyl.
In some embodiments of Formulas I, R11For：Hydrogen；Halogen；Oxo；Hydroxyl；Or C1-6Alkyl, it can be unsubstituted Or substituted one or more times by halogen or oxo.
In some embodiments of Formulas I, R11For：Hydrogen；Halogen；Carboxyl；C1-6Alkyl-carbonyl；C1-6Alkoxy-carbonyl； Oxo；Hydroxyl；Amino carbonyl；N-C1-6Alkyl-aminocarbonyl；- the C of N, N- bis-1-6Alkyl-aminocarbonyl；Or C1-6Alkyl, it can To be unsubstituted or be substituted one or more times by halogen or oxo.
In some embodiments of Formulas I, R11For：Hydrogen；Halogen；Or C1-6Alkyl.
In some embodiments of Formulas I, R11For：Hydrogen；C1-6Alkyl；Or halogen.
In some embodiments of Formulas I, R11For：Hydrogen；Or C1-6Alkyl.
In some embodiments of Formulas I, R11For hydrogen.
In some embodiments of Formulas I, R11For C1-6Alkyl
In some embodiments of Formulas I, R11For methyl.
In some embodiments of Formulas I, R11For halogen.
In some embodiments of Formulas I, R11For oxo.
In some embodiments of Formulas I, R11For C1-6Alkyl-sulfonylamino.
In some embodiments of Formulas I, R11For C1-6Alkyl-sulfonylamino-C1-6Alkyl.
In some embodiments of Formulas I, R11For cyano group.
In some embodiments of Formulas I, R11For hydroxyl-C16Alkyl.
In some embodiments of Formulas I, R11For N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, R11For N- hydroxyls-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, R11For N-C1-6Alkoxy-amino carbonyl.
In some embodiments of Formulas I, R12For：Hydrogen；Or C1-6Alkyl.
In some embodiments of Formulas I, R12For hydrogen.
In some embodiments of Formulas I, R12For halogen.
In some embodiments of Formulas I, R12For carboxyl.
In some embodiments of Formulas I, R12For C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, R12For C1-6Alkoxy-carbonyl.
In some embodiments of Formulas I, R12For oxo.
In some embodiments of Formulas I, R12For hydroxyl.
In some embodiments of Formulas I, R12For amino carbonyl.
In some embodiments of Formulas I, R12For N-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, R12For the N ,-C of N- bis-1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, R12For cyano group.
In some embodiments of Formulas I, R12For hydroxyl-C1-6Alkyl.
In some embodiments of Formulas I, R12For N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, R12For N- hydroxyls-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, R12For N-C1-6Alkoxy-amino carbonyl.
In some embodiments of Formulas I, R12For C1-6Alkyl.
In some embodiments of Formulas I, R12For methyl.
In some embodiments of Formulas I, R10And R113,4,5,6 or 7 yuan are formed together with the atom connected with them to satisfy Sum or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optional By RiSubstitution is one or more times.
In some embodiments of Formulas I, R10And R114,5,6 or 7 yuan of rings are formed together with the atom connected with them.
In some embodiments of Formulas I, R10And R11Double bond is formed together with the atom connected with them.
In some embodiments of Formulas I, R13For hydrogen.
In some embodiments of Formulas I, R13For C1-6Alkyl.
In some embodiments of Formulas I, Ra、Rb、RcAnd RdEach stand alone as：Hydrogen；Or C1-6Alkyl.
In some embodiments of Formulas I, RaFor hydrogen.
In some embodiments of Formulas I, RaFor C1-6Alkyl.
In some embodiments of Formulas I, RbFor hydrogen.
In some embodiments of Formulas I, RbFor C1-6Alkyl.
In some embodiments of Formulas I, RcFor hydrogen.
In some embodiments of Formulas I, RcFor C1-6Alkyl.
In some embodiments of Formulas I, RbAnd Rc3,4,5,6 or 7 yuan of saturations are formed together with the atom connected with them Or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by Ri Substitution is one or more times.
In some embodiments of Formulas I, RbAnd RcOne of and R7And R8One of and their atoms for being connected shape together Into 3,4,5,6 or 7 yuan of saturations or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S-'s is miscellaneous Atom, it can be optionally by RiSubstitution is one or more times.
In some embodiments of Formulas I, RbAnd RcOne of and R5And R6One of and their atoms for being connected shape together Into 3,4,5,6 or 7 yuan of saturations or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S-'s is miscellaneous Atom, it can be optionally by RiSubstitution is one or more times.
In some embodiments of Formulas I, RdFor hydrogen.
In some embodiments of Formulas I, RdFor C1-6Alkyl.
In some embodiments of Formulas I, each ReStand alone as：Hydrogen；C1-6Alkyl；Halogen；Or halo-C1-6Alkyl.
In some embodiments of Formulas I, each ReStand alone as：Hydrogen；C1-6Alkyl；Or halogen.
In some embodiments of Formulas I, each ReStand alone as：Hydrogen；Or halogen.
In some embodiments of Formulas I, each ReStand alone as：Hydrogen；Or fluorine.
In some embodiments of Formulas I, ReFor hydrogen.
In some embodiments of Formulas I, ReFor C1-6Alkyl.
In some embodiments of Formulas I, ReFor halogen.
In some embodiments of Formulas I, ReFor C1-6Alkoxy.
In some embodiments of Formulas I, ReFor cyano group.
In some embodiments of Formulas I, ReFor halo-C1-6Alkyl.
In some embodiments of Formulas I, RfFor：Hydrogen；Halogen；C1-6Alkyl；C1-6Alkoxy；Or halo-C1-6Alkyl.
In some embodiments of Formulas I, RfFor：Hydrogen；C1-6Alkyl；Or halo-C1-6Alkyl.
In some embodiments of Formulas I, RfFor：Hydrogen；Fluorine；Methyl；Methoxyl group；Or trifluoromethyl.
In some embodiments of Formulas I, RfFor：Hydrogen；Methyl；Or trifluoromethyl.
In some embodiments of Formulas I, RfFor：Hydrogen；Or C1-6Alkyl.
In some embodiments of Formulas I, RfFor hydrogen.
In some embodiments of Formulas I, RfFor C1-6Alkyl.
In some embodiments of Formulas I, RfFor halo-C1-6Alkyl.
In some embodiments of Formulas I, RfFor halogen.
In some embodiments of Formulas I, RfFor C1-6Alkoxy.
In some embodiments of Formulas I, RfFor methyl.
In some embodiments of Formulas I, RfFor trifluoromethyl.
In some embodiments of Formulas I, RfFor methoxyl group.
In some embodiments of Formulas I, RfFor fluorine.
In some embodiments of Formulas I, RgFor：C1-6Alkyl；C3-6Cycloalkyl；C3-6Cycloalkenyl group；C3-6Cycloalkyl-C1-6 Alkyl；Halogen；C1-6Alkyl-carbonyl；C3-6Cycloalkyl-carbonyl；C3-6Cycloalkyl-C1-6Alkyl-carbonyl；Cyano group-C1-6Alkyl-carbonyl Base；Hydroxyl-C1-6Alkyl-carbonyl；C1-6Alkoxy -C1-6Alkyl-carbonyl；Carboxyl；N- cyano group-amino carbonyl；N- cyano group-N-C1-6 Alkyl-aminocarbonyl；N-C1-6Alkyl-ethanamidine base；N, N '-two-C1-6Alkyl-ethanamidine base；N '-cyano group-N-C1-6Alkyl-ethanamidine Base；N'- hydroxy-acetamidine bases；N'-C1-6Alkoxy-ethanamidine base；N'- hydroxy-ns-C1-6Alkyl-ethanamidine base；N'-C1-6Alkoxy- N-C1-6Alkyl-ethanamidine base；2- nitros -1-N-C1-6Alkyl amino-vinyl；Formoxyl；C1-6Alkyl-sulfonyl base；C3-6Cycloalkanes Base-sulfonyl；C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；C1-6Alkyl-sulfonyl base-C1-6Alkyl；Amino carbonyl；N- hydroxyls-ammonia Base carbonyl；N-C1-6Alkoxy-amino carbonyl；N-C1-6Alkyl-aminocarbonyl；N- hydroxy-ns-C1-6Alkyl-aminocarbonyl；N- C1-6Alkoxy-N-C1-6Alkyl-aminocarbonyl；- the C of N, N- bis-1-6Alkyl-aminocarbonyl；Amino-sulfonyl；N-C1-6Alkyl-ammonia Base sulfonyl；- the C of N, N- bis-1-6Alkyl-amino sulfonyl；Cyano group；C1-6Alkoxy；C1-6Alkyl-sulfonylamino；N-C1-6Alkane Base-sulfonyl amino carbonyl；N-(C1-6Alkyl-sulfonyl base)-N-C1-6Alkyl-aminocarbonyl；N-(C1-6Alkyl-sulfonyl base)-ammonia Base-C1-6Alkyl；Amino；N-C1-6Alkyl-amino；- the C of N, N- bis-1-6Alkyl-amino；Halo-C1-6Alkyl；Heterocyclic radical；Heteroaryl Base；Or hydroxyl；Wherein C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；Wherein heterocyclic radical, heteroaryl Base, C3-6Cycloalkyl, C3-6Cycloalkenyl group and C3-6Cycloalkyl-C1-6Moieties can be unsubstituted or by RiSubstitute one or more It is secondary.
In some embodiments of Formulas I, RgFor：Hydrogen；C1-6Alkyl；C3-6Cycloalkyl；C3-6Cycloalkyl-C1-6Alkyl；Halogen Element；C1-6Alkyl-carbonyl；C3-6Cycloalkyl-carbonyl；C3-6Cycloalkyl-C1-6Alkyl-carbonyl；C1-6Alkyl-sulfonyl base；C3-6Cycloalkanes Base-sulfonyl；C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；Amino carbonyl；N-C1-6Alkyl-aminocarbonyl；- the C of N, N- bis-1-6Alkane Base-amino carbonyl；Amino-sulfonyl；N-C1-6Alkyl-amino sulfonyl；- the C of N, N- bis-1-6Alkyl-amino sulfonyl；Cyano group； C1-6Alkoxy；C1-6Alkyl-sulfonylamino；Amino；N-C1-6Alkyl-amino；- the C of N, N- bis-1-6Alkyl-amino；Halo-C1-6 Alkyl；Or hydroxyl；Wherein C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；Wherein C3-6Cycloalkyl And C3-6Cycloalkyl-C1-6Moieties can be unsubstituted or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RgFor：Hydrogen；Halogen；C1-6Alkyl；Hydroxyl；C1-6Alkoxy；Or halo-C1-6 Alkyl.
In some embodiments of Formulas I, RgFor：Hydrogen；C1-6Alkyl；Halogen；Carbonylamino；C1-6Alkoxy；Heteroaryl； C1-6Alkyl-carbonylamino；Carbonylamino；Or hydroxyl.
In some embodiments of Formulas I, RgFor hydrogen.
In some embodiments of Formulas I, RgFor C1-6Alkyl.
In some embodiments of Formulas I, RgFor C3-6Cycloalkyl, it can be unsubstituted or by RiSubstitute one or more It is secondary.
In some embodiments of Formulas I, RgFor C3-6Cycloalkyl-C1-6Alkyl, it can be unsubstituted or by RiTake In generation, is one or more times.
In some embodiments of Formulas I, RgFor halogen.
In some embodiments of Formulas I, RgFor C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, RgFor C3-6Cycloalkyl-carbonyl, wherein C3-6Cycloalkyl moiety can not taken Generation or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RgFor C3-6Cycloalkyl-C1-6Alkyl-carbonyl, wherein C3-6Cycloalkyl-C1-6Alkane Base section can be unsubstituted or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RgFor C1-6Alkyl-sulfonyl base.
In some embodiments of Formulas I, RgFor C3-6Cycloalkyl-sulfonyl.
In some embodiments of Formulas I, RgFor C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base.
In some embodiments of Formulas I, RgFor amino carbonyl.
In some embodiments of Formulas I, RgFor N-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RgFor the N ,-C of N- bis-1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RgFor amino-sulfonyl.
In some embodiments of Formulas I, RgFor N-C1-6Alkyl-amino sulfonyl.
In some embodiments of Formulas I, RgFor the N ,-C of N- bis-1-6Alkyl-amino sulfonyl.
In some embodiments of Formulas I, RgFor cyano group.
In some embodiments of Formulas I, RgFor C1-6Alkoxy.
In some embodiments of Formulas I, RgFor C1-6Alkyl-sulfonylamino.
In some embodiments of Formulas I, RgFor amino.
In some embodiments of Formulas I, RgFor N-C1-6Alkyl-amino.
In some embodiments of Formulas I, RgFor the N ,-C of N- bis-1-6Alkyl-amino.
In some embodiments of Formulas I, RgFor halo-C1-6Alkyl.
In some embodiments of Formulas I, RgFor hydroxyl.
In some embodiments of Formulas I, RgFor C3-6Cycloalkyl, it can be unsubstituted or by RiSubstitute one or more It is secondary.
In some embodiments of Formulas I, RgFor cyano group-C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, RgFor hydroxyl-C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, RgFor C1-6Alkoxy -C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, RgFor carboxyl.
In some embodiments of Formulas I, RgFor N- cyano group-amino carbonyl.
In some embodiments of Formulas I, RgFor N- cyano group-N-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RgFor N-C1-6Alkyl-ethanamidine base.
In some embodiments of Formulas I, RgFor the N ,-C of N '-two1-6Alkyl-ethanamidine base.
In some embodiments of Formulas I, RgFor N '-cyano group-N-C1-6Alkyl-ethanamidine base.
In some embodiments of Formulas I, RgFor N'- hydroxy-acetamidine bases.
In some embodiments of Formulas I, RgFor N'-C1-6Alkoxy-ethanamidine base.
In some embodiments of Formulas I, RgFor N'- hydroxy-ns-C1-6Alkyl-ethanamidine (acetimidamide)；N'- C1-6Alkoxy-N-C1-6Alkyl-ethanamidine base.
In some embodiments of Formulas I, RgFor 2- nitros -1-N-C1-6Alkyl amino-vinyl.
In some embodiments of Formulas I, RgFor C1-6Alkyl-sulfonyl base-C1-6Alkyl.
In some embodiments of Formulas I, RgFor N- hydroxy-amino carbonyls.
In some embodiments of Formulas I, RgFor N-C1-6Alkoxy-amino carbonyl.
In some embodiments of Formulas I, RgFor N- hydroxy-ns-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RgFor N-C1-6Alkoxy-N-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RgFor N-C1-6Alkyl-sulfonylamino carbonyl.
In some embodiments of Formulas I, RgFor N- (C1-6Alkyl-sulfonyl base)-N-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RgFor amino carbonyl-C1-6Alkyl.
In some embodiments of Formulas I, RgFor N-C1-6Alkyl-aminocarbonyl-C1-6Alkyl
In some embodiments of Formulas I, RgFor the N ,-C of N- bis-1-6Alkyl-aminocarbonyl-C1-6Alkyl.
In some embodiments of Formulas I, RgFor C1-6Alkoxy-carbonyl.
In some embodiments of Formulas I, RgFor carbonylamino.
In some embodiments of Formulas I, RgFor heterocyclic radical, it can be unsubstituted or by RiSubstitution is one or more times.
In the embodiment of Formulas I, wherein RgFor heterocyclic radical, the heterocyclic radical can be oxetanylmethoxy, tetrahydrofuran base, THP trtrahydropyranyl, azelidinyl, pyrrolidinyl, piperidyl, azepineOr piperazinyl, each of which can be unsubstituted Or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RgFor heteroaryl, it can be unsubstituted or by RiSubstitution is one or more times.
In the embodiment of Formulas I, wherein RgFor heteroaryl, the heteroaryl can be pyridine radicals, pyrimidine radicals, triazine radical, Pyrrole radicals, imidazole radicals, pyrazolyl, triazolyl, oxazolyls, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazolyl group Or tetrazole radical, each of which can be unsubstituted or by RiSubstitution is one or more times.
In the embodiment of Formulas I, wherein RgFor heteroaryl, the heteroaryl can be imidazole radicals, pyrazolyl, triazolyl, Oxazolyl, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazolyl group or tetrazole radical, each of which can be not Substitution or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RgFor triazolyl.
In some embodiments of Formulas I, RgFor [1,2,4] triazole-4-yl.
In some embodiments of Formulas I, RgFor [1,2,4] triazole -3- bases.
In some embodiments of Formulas I, RgFor 4- methyl-[1,2,4] triazole -3- bases.
In some embodiments of Formulas I, RgFor [1,2,4] triazol-1-yl.
In some embodiments of Formulas I, RgFor [1,2,3] triazol-1-yl.
In some embodiments of Formulas I, RgFor [1,2,3] triazole-4-yl.
In some embodiments of Formulas I, RgFor 4- methyl-[1,2,4] triazole -3- bases.
In some embodiments of Formulas I, RgFor pyrazolyl.
In some embodiments of Formulas I, RgFor pyrazole-3-yl.
In some embodiments of Formulas I, RgFor pyrazol-1-yl.
In some embodiments of Formulas I, RgFor pyrazoles -4- bases.
In some embodiments of Formulas I, RgFor imidazole radicals.
In some embodiments of Formulas I, RgFor imidazoles -1- bases.
In some embodiments of Formulas I, RgFor 1- methyl-imidazoles -2- bases.
In some embodiments of Formulas I, RgWei isoxazolyls.
In some embodiments of Formulas I, RgFor 3- hydoxyisoxazole -5- bases.
In some embodiments of Formulas I, RgWei oxadiazolyls.
In some embodiments of Formulas I, RgFor [1,2,4] oxadiazole -5- bases.
In some embodiments of Formulas I, RgFor [1,2,4] oxadiazole -3- bases.
In some embodiments of Formulas I, RgFor [1,2,3] oxadiazole -2- bases.
In some embodiments of Formulas I, RgFor [1,2,3] oxadiazole -2- ketone -5- bases.
In some embodiments of Formulas I, RgFor tetrazole radical.
In some embodiments of Formulas I, RgFor tetrazolium -5- bases.
In some embodiments of Formulas I, RgFor tetrazolium -1- bases.
In some embodiments of Formulas I, RgFor tetrazolium -2- bases.
In some embodiments of Formulas I, RgFor pyrazolyl.
In some embodiments of Formulas I, RgFor pyridazinyl.
In some embodiments of Formulas I, RgFor triazine radical.
In some embodiments of Formulas I, RgFor C2-6Alkenyl.
In some embodiments of Formulas I, RfAnd Rg3,4,5,6 or 7 yuan of saturations are formed together with the atom connected with them Or fractional saturation ring.
In some embodiments of Formulas I, RfAnd Rg3 yuan of rings are formed together with the atom connected with them.
In some embodiments of Formulas I, RfAnd Rg4 yuan of rings are formed together with the atom connected with them.
In some embodiments of Formulas I, RfAnd Rg5 yuan of rings are formed together with the atom connected with them.
In some embodiments of Formulas I, RfAnd Rg6 yuan of rings are formed together with the atom connected with them.
In some embodiments of Formulas I, RfAnd Rg7 yuan of rings are formed together with the atom connected with them.
In some embodiments of Formulas I, RfAnd RgOxo is formed together with the atom connected with them.
In some embodiments of Formulas I, RhFor：Hydrogen；C1-6Alkyl；C3-6Cycloalkyl；C3-6Cycloalkenyl group；C3-6Cycloalkyl- C1-6Alkyl；C1-6Alkyl-carbonyl；C3-6Cycloalkyl-carbonyl；C3-6Cycloalkyl-C1-6Alkyl-carbonyl；Cyano group-C1-6Alkyl-carbonyl； Hydroxyl-C1-6Alkyl-carbonyl；C1-6Alkoxy -C1-6Alkyl-carbonyl；N- cyano group-amino carbonyl；N- cyano group-N-C1-6Alkyl-ammonia Base carbonyl；N-C1-6Alkyl-ethanamidine base；N, N '-two-C1-6Alkyl-ethanamidine base；N '-cyano group-N-C1-6Alkyl-ethanamidine base；N'- hydroxyls Base-ethanamidine base；N'-C1-6Alkoxy-ethanamidine base；N'- hydroxy-ns-C1-6Alkyl-ethanamidine base；N'-C1-6Alkoxy-N-C1-6Alkane Base-ethanamidine base；2- nitros -1-N-C1-6Alkyl amino-vinyl；Formoxyl；C1-6Alkyl-sulfonyl base；C3-6Cycloalkyl-sulphonyl Base；C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；C1-6Alkyl-sulfonyl base-C1-6Alkyl；Amino carbonyl；N- hydroxy-amino carbonyls； N-C1-6Alkoxy-amino carbonyl；N-C1-6Alkyl-aminocarbonyl；N- hydroxy-ns-C1-6Alkyl-aminocarbonyl；N-C1-6Alcoxyl Base-N-C1-6Alkyl-aminocarbonyl；- the C of N, N- bis-1-6Alkyl-aminocarbonyl；Amino-sulfonyl；N-C1-6Alkyl-amino sulphonyl Base；- the C of N, N- bis-1-6Alkyl-amino sulfonyl；Cyano group；C1-6Alkyl-sulfonylamino；C1-6Alkyl-sulfonylamino-C1-6Alkane Base；N-(C1-6Alkyl-sulfonyl base) amino carbonyl；N-(C1-6Alkyl-sulfonyl base)-N-C1-6Alkyl-aminocarbonyl；N-(C1-6Alkane Base-sulfonyl)-amino-C1-6Alkyl；Halo-C1-6Alkyl；Heterocyclic radical；Or heteroaryl；Wherein C1-6Moieties can be not Substitution or be optionally substituted by halogen one or more times；Wherein heterocyclic radical, heteroaryl, C3-6Cycloalkyl, C3-6Cycloalkenyl group and C3-6Cycloalkanes Base-C1-6Moieties can be unsubstituted or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RhFor：Hydrogen；C1-6Alkyl；C3-6Cycloalkyl；C3-6Cycloalkyl-C1-6Alkyl；C1-6 Alkyl-carbonyl；C3-6Cycloalkyl-carbonyl；C3-6Cycloalkyl-C1-6Alkyl-carbonyl；C1-6Alkyl-sulfonyl base；C3-6Cycloalkyl-sulphonyl Base；C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；Amino carbonyl；N-C1-6Alkyl-aminocarbonyl；- the C of N, N- bis-1-6Alkyl-amino carbonyl Base；Amino-sulfonyl；N-C1-6Alkyl-amino sulfonyl；Or-the C of N, N- bis-1-6Alkyl-amino sulfonyl；Wherein C1-6Alkyl portion It point can be unsubstituted or be optionally substituted by halogen one or more times；Wherein C3-6Cycloalkyl and C3-6Cycloalkyl-C1-6Moieties can To be unsubstituted or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RhFor：C1-6Alkyl-carbonyl；C3-6Cycloalkyl-carbonyl；C3-6Cycloalkyl-C1-6 Alkyl-carbonyl；C1-6Alkyl-sulfonyl base；C3-6Cycloalkyl-sulfonyl；C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；Amino carbonyl； N-C1-6Alkyl-aminocarbonyl；Or-the C of N, N- bis-1-6Alkyl-aminocarbonyl；Amino-sulfonyl；N-C1-6Alkyl-amino sulfonyl； Or-the C of N, N- bis-1-6Alkyl-amino sulfonyl；Wherein C3-6Cycloalkyl and C3-6Cycloalkyl-C1-6Moieties can be each not Substitution or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RhFor：C1-6Alkyl-carbonyl；C3-6Cycloalkyl-carbonyl；C3-6Cycloalkyl-C1-6 Alkyl-carbonyl；C1-6Alkyl-sulfonyl base；C3-6Cycloalkyl-sulfonyl；Or C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；Wherein C3-6 Cycloalkyl and C3-6Cycloalkyl-C1-6Moieties can be each unsubstituted or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RhFor：C1-6Alkyl-carbonyl；C3-6Cycloalkyl-carbonyl；Or C3-6Cycloalkyl- C1-6Alkyl-carbonyl；Wherein C3-6Cycloalkyl and C3-6Cycloalkyl-C1-6Moieties can be each unsubstituted or by RiTake In generation, is one or more times.
In some embodiments of Formulas I, RhFor hydrogen.
In some embodiments of Formulas I, RhFor C1-6Alkyl.
In some embodiments of Formulas I, RhFor C3-6Cycloalkyl, it can be unsubstituted or by RiSubstitute one or more It is secondary.
In some embodiments of Formulas I, RhFor C3-6Cycloalkyl-C1-6Alkyl.
In some embodiments of Formulas I, RhFor C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, RhFor C3-6Cycloalkyl-carbonyl.
In some embodiments of Formulas I, RhFor C3-6Cycloalkyl-C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, RhFor C1-6Alkyl-sulfonyl base.
In some embodiments of Formulas I, RhFor C3-6Cycloalkyl-sulfonyl.
In some embodiments of Formulas I, RhFor C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base.
In some embodiments of Formulas I, RhFor amino carbonyl.
In some embodiments of Formulas I, RhFor N-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RhFor the N ,-C of N- bis-1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RhFor amino-sulfonyl.
In some embodiments of Formulas I, RhFor N-C1-6Alkyl-amino sulfonyl.
In some embodiments of Formulas I, RhFor the N ,-C of N- bis-1-6Alkyl-amino sulfonyl.
In some embodiments of Formulas I, RhFor C3-6Cycloalkenyl group.
In some embodiments of Formulas I, RhFor cyano group-C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, RhFor hydroxyl-C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, RhFor C1-6Alkoxy -C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, RhFor N- cyano group-amino carbonyl.
In some embodiments of Formulas I, RhFor N- cyano group-N-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RhFor N-C1-6Alkyl-ethanamidine base.
In some embodiments of Formulas I, RhFor the N ,-C of N '-two1-6Alkyl-ethanamidine base.
In some embodiments of Formulas I, RhFor N '-cyano group-N-C1-6Alkyl-ethanamidine base.
In some embodiments of Formulas I, RhFor N'- hydroxy-acetamidine bases.
In some embodiments of Formulas I, RhFor N'-C1-6Alkoxy-ethanamidine base.
In some embodiments of Formulas I, RhFor N'- hydroxy-ns-C1-6Alkyl-ethanamidine base.
In some embodiments of Formulas I, RhFor N'-C1-6Alkoxy-N-C1-6Alkyl-ethanamidine base.
In some embodiments of Formulas I, RhFor 2- nitros -1-N-C1-6Alkyl amino-vinyl.
In some embodiments of Formulas I, RhFor C1-6Alkyl-sulfonyl base-C1-6Alkyl.
In some embodiments of Formulas I, RhFor N- hydroxy-amino carbonyls.
In some embodiments of Formulas I, RhFor N-C1-6Alkoxy-amino carbonyl.
In some embodiments of Formulas I, RhFor N- hydroxy-ns-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RhFor N-C1-6Alkoxy-N-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RhFor C1-6Alkyl-sulfonylamino-C1-6Alkyl.
In some embodiments of Formulas I, RhFor N- (C1-6Alkyl-sulfonyl base) amino carbonyl.
In some embodiments of Formulas I, RhFor N- (C1-6Alkyl-sulfonyl base)-N-C1-6Alkyl-aminocarbonyl.
In some embodiments of Formulas I, RhFor amino carbonyl-C1-6Alkyl.
In some embodiments of Formulas I, RhFor N-C1-6Alkyl-aminocarbonyl-C1-6Alkyl
In some embodiments of Formulas I, RhFor the N ,-C of N- bis-1-6Alkyl-aminocarbonyl-C1-6Alkyl.
In some embodiments of Formulas I, RhFor C1-6Alkoxy-carbonyl.
In some embodiments of Formulas I, RhFor heterocyclic radical, it can be unsubstituted or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RhFor heteroaryl, it can be unsubstituted or by RiSubstitution is one or more times.
In the embodiment of Formulas I, wherein RhFor heteroaryl, the heteroaryl can be pyridine radicals, pyrimidine radicals, pyrrole radicals, Imidazole radicals, pyrazolyl, triazolyl, oxazolyls, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazolyl group or tetrazolium Base, each of which can be unsubstituted or by RiSubstitution is one or more times.
In the embodiment of Formulas I, wherein RhFor heteroaryl, the heteroaryl can be imidazole radicals, pyrazolyl, triazolyl, Oxazolyl, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazolyl group or tetrazole radical, each of which can be not Substitution or by RiSubstitution is one or more times.
In some embodiments of Formulas I, RhFor acetyl group.
In some embodiments of Formulas I, RhFor mesyl.
In some embodiments of Formulas I, RhFor cyclopropyl carbonyl.
In some embodiments of Formulas I, RhWith R10And R11One of and their atoms for being connected form 4,5,6 together 7 yuan of aromatics, fractional saturation or undersaturated ring.
In some embodiments of Formulas I, RhWith R10And R11One of and their atoms for being connected form 4 yuan together Ring.
In some embodiments of Formulas I, RhWith R10And R11One of and their atoms for being connected form 5 yuan together Ring.
In some embodiments of Formulas I, RhWith R10And R11One of and their atoms for being connected form 6 yuan together Ring.
In some embodiments of Formulas I, RhWith R10And R11One of and their atoms for being connected form 7 yuan together Ring.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Formed 4,5,6 or 7 yuan of aromatics, fractional saturation or undersaturated ring.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Form 5 or 6 yuan of aromatic rings.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Form 5 yuan of aromatic rings.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Form 6 yuan of aromatic rings.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Form 5 or 6 yuan of saturated rings.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Form 5 yuan of saturated rings.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Form 6 yuan of saturated rings.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Form 4 yuan of rings.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Form 5 yuan of rings.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Form 6 yuan of rings.
In some embodiments of Formulas I, RfAnd RgOne of and R10And R11One of and their atoms for being connected together Form 7 yuan of rings.
In some embodiments of Formulas I, RiFor：C1-6Alkyl；Halogen；Oxo；Hydroxyl；Acetyl group；Or C1-6Alkoxy.
In some embodiments of Formulas I, RiFor C1-6Alkyl.
In some embodiments of Formulas I, RiFor halogen.
In some embodiments of Formulas I, RiFor C1-6Alkoxy.
In some embodiments of Formulas I, RiFor halo-C1-6Alkyl.
In some embodiments of Formulas I, RiFor oxo.
In some embodiments of Formulas I, RiFor hydroxyl.
In some embodiments of Formulas I, RiFor acetyl group.
In some embodiments of Formulas I, RiFor C1-6Alkyl-carbonyl.
In some embodiments of Formulas I, RiFor amino-carbonyl.
In some embodiments of Formulas I, RiFor hydroxyl-C1-6Alkyl.
In some embodiments of Formulas I, RiFor cyano group.
In some embodiments of Formulas I, RiFor halo-C1-6Alkyl.
In some embodiments of Formulas I, RiFor C3-6Cycloalkyl.
In some embodiments of Formulas I, RjAnd RkEach stand alone as：Hydrogen；Or methyl.
In some embodiments of Formulas I, RjFor hydrogen.
In some embodiments of Formulas I, RkFor hydrogen.
In some embodiments of Formulas I, RmFor：C1-6Alkyl；Oxo；Hydroxyl；Amino；Or hydroxyl-C1-6Alkyl.
In some embodiments of Formulas I, RmFor：C1-6Alkyl；Or oxo.
In some embodiments of Formulas I, RmFor C1-6Alkyl.
In some embodiments of Formulas I, RmFor oxo.
In some embodiments of Formulas I, RmFor hydroxyl.
In some embodiments of Formulas I, RmFor amino.
In some embodiments of Formulas I, RmFor C3-6Cycloalkyl.
In some embodiments of Formulas I, RmFor amino-C1-6Alkyl.
In some embodiments of Formulas I, RmFor hydroxyl-C1-6Alkyl.
In some embodiments of Formulas I, RmFor hydroxyl-C1-6Alkenyl.
In some embodiments of Formulas I, RmFor C1-6Alkoxy carbonyl-C1-6Alkyl.
In some embodiments of Formulas I, RmFor halogen.
In some embodiments of Formulas I, RmFor amino carbonyl-C1-6Alkyl.
In some embodiments of Formulas I, RmFor C1-6Alkoxy carbonyl.
In some embodiments of Formulas I, RmFor cyano group-C1-6Alkyl.
In some embodiments of Formulas I, RnFor C1-6Alkyl.
In some embodiments of Formulas I, RnFor oxo.
In some embodiments of Formulas I, RnFor hydroxyl.
In some embodiments of Formulas I, RnFor amino.
In some embodiments of Formulas I, RnFor C3-6Cycloalkyl.
In some embodiments of Formulas I, RnFor amino-C1-6Alkyl.
In some embodiments of Formulas I, RnFor hydroxyl-C1-6Alkyl.
In some embodiments of Formulas I, RnFor hydroxyl-C1-6Alkenyl.
In some embodiments of Formulas I, RnFor C1-6Alkoxy carbonyl-C1-6Alkyl.
In some embodiments of Formulas I, RnFor halogen.
In some embodiments of Formulas I, RnFor amino carbonyl-C1-6Alkyl.
In some embodiments of Formulas I, RnFor C1-6Alkoxy carbonyl.
In some embodiments of Formulas I, RpFor hydrogen.
In some embodiments of Formulas I, RpFor C1-6Alkyl.
In certain embodiments, target compound can be Formula II：
Wherein s is 0-3, ReFor：C1-6Alkyl；C1-6Alkoxy；Hydroxyl；Halogen；Hydroxyl-C1-6Alkyl；Or cyano group；
p、q、r、A、Y、Z、Het、R1、R2、R3、R9、R10、R11And RmAs defined herein.
In certain embodiments, target compound can be formula III：
Wherein p, q, r, s, Y, Z, Het, R1、R2、R3、R9、R10、R11、ReAnd RmAs defined herein.
In certain embodiments, target compound can be formula IV：
Wherein p, q, r, s, Y, Z, Het, R3、R9、R10、R11、ReAnd RmAs defined herein.
In certain embodiments, target compound can be Formula V：
Wherein p, q, r, s, Z, Het, R3、R9、R10、R11、Re、Rf、RgAnd RmAs defined herein.
In certain embodiments, target compound can be Formula IV：
Wherein p, q, r, s, Z, Het, R3、R9、R10、R11、Re、RhAnd RmAs defined herein.
In certain embodiments, target compound can be Formula VII：
Wherein p, q, r, s, Z, Het, R3、R9、R10、R11、ReAnd RmAs defined herein.
In certain embodiments, target compound can be Formula VIII：
Wherein p, q, r, s, Z, Het, R3、R9、R10、R11、Re、Rf、RgAnd RmAs defined herein.
In certain embodiments, target compound can be Formula VIII：
Wherein p, q, r, s, Z, Ar, R3、R9、R10、R11、Re、Rf、RgAnd RmAs defined herein.
In certain embodiments, target compound can be formula III a：
Wherein p, q, r, s, Y, Z, Het, r, R1、R2、R3、R9、R10、R11、ReAnd RmAs defined herein.
In certain embodiments, target compound can be formula IV a：
Wherein p, q, r, s, Y, Z, Het, R3、R9、R10、R11、ReAnd RmAs defined herein.
In certain embodiments, target compound can be Formula V a：
Wherein p, q, r, s, Z, Het, R3、R9、R10、R11、Re、Rf、RgAnd RmAs defined herein.
In certain embodiments, target compound can be Formula IV a：
Wherein p, q, r, s, Z, Het, R3、R9、R10、R11、Re、RhAnd RmAs defined herein.
In certain embodiments, target compound can be Formula VII a：
Wherein p, q, r, s, Z, Het, R3、R9、R10、R11、ReAnd RmAs defined herein.
In certain embodiments, target compound can be Formula VIII a：
Wherein p, q, r, s, Z, Het, R3、R9、R10、R11、Re、Rf、RgAnd RmAs defined herein.
In certain embodiments, target compound can be Formula IX a：
Wherein p, q, r, s, Z, Het, R3、R9、R10、R11、Re、Rf、RgAnd RmAs defined herein.
Method
The present invention is also provided for treating by RORc is receptor-mediated or the disease related to RORc acceptors or the side of illness Method, methods described include giving the compounds of this invention of the individual effective dose of needs.
The disease can be arthritis, such as rheumatoid arthritis, arthritis vertebralis or osteoarthritis.
The disease can be asthma or COPD.
The disease can be psoriasis, lupus, She Gelunshi diseases, IBS or idiopathic pulmonary fibrosis.
The disease can be muscle gelling.
According to the representative compound of the inventive method as shown in following EXPERIMENTAL EXAMPLE.
Synthesis
The compounds of this invention can pass through a variety of sides described in illustrative synthetic reaction flow shown and described below It is prepared by method.
Raw material and reagent for preparing these compounds generally can be from commercial supplier such as Aldrich Chemical Co. obtain, or by method known to those skilled in the art according to preparation described in following bibliography：Such as Fieser And Fieser organic synthesis reagent (Reagents for Organic Synthesis)；Wiley&Sons：New York, 1991, the 1-15 volumes；Rodd carbon compound is chemical (Chemistry of Carbon Compounds), Elsevier Science Publishers, 1989,1-5 volumes and its addendum；Organic reaction (Organic Reactions), Wiley＆ Sons：New York, 1991, the 1-40 volumes.Following synthetic reaction flow only can be used for synthesizing the compounds of this invention Certain methods explanation, various modifications can be carried out to these synthetic reaction flows, can be to reference to present disclosure Those skilled in the art provide suggestion.
If desired, can use routine techniques (including but not limited to filtering, distillation, crystallization, chromatography etc.) separate with Purify the raw material and intermediate of synthetic reaction flow.These materials can use conventional meanses to characterize, including physical constant and light Modal data.
Unless there are opposite regulation, reaction described here can be carried out in inert environments, under atmospheric pressure, reaction temperature Scope at about -78 DEG C to about 150 DEG C, e.g., from about 0 DEG C to about 125 DEG C or advantageously at about room temperatures (or environment temperature), example Such as from about 20 DEG C.
Following flow A illustrates a kind of synthetic method for preparing specific compound of formula I, and wherein LG is leaving group Group, such as halo, sulfonate group etc., m, n, p, q, A, X1、X2、X3、X4、Z、Ar、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、 RbAnd RcAs defined herein.
Flow A
In flow step A 1, alkylamine a and arylsulfonyl chloride b reacts to form sulfonamide compounds c.The reaction of step 1 It can be carried out in polar proton inert solvent (such as THF or dichloromethane), in the presence of tertiary amine base or weak base (such as potassium carbonate). In certain embodiments, the leaving group of compound a can be bromine.Similarly, compound b chloro group is in some implementations It can be substituted in scheme by other halogens or leaving group.
Cyclization is carried out in step 2, obtains thiazine hydride compounds d.Cyclisation can be at highly basic (such as alkyl lithium reagents) In the presence of, in anhydrous conditions using polar proton inert solvent realize.
In step 3, thiazine hydride compounds c and arylalkyl halide compound e reacts, and obtains aralkyl thiazan f. The reaction of step 3 can be carried out under the conditions of anhydrous polar aprotic solvent in the presence of highly basic such as sodium hydride.Compound e bromine It can be substituted for group by other suitable leaving groups used in the art.
Thiazine hydride compounds can use reagent g processing in step 4A, and to provide sultam compound h, it is this hair Bright compound of formula I.In wherein A is oxygen so that reagent g is the embodiment of cyclic alcohol, step 4A reaction can be Copper catalyst and hydrophobic solvent are used in the presence of cesium carbonate or similar alkali.
Or step 4B can be carried out, wherein thiazine hydride compounds f and compound i is alkylated reaction, obtains in sulphur Amide compound j, it is compound of formula I of the invention.The reaction of the step can be under Buchwald reaction conditions using conjunction Suitable palladium catalyst is carried out.
Following flow B is shown is available for another synthetic method for preparing specific compound of formula I, wherein TBS Three-(tert-butyl)-silicyl, m, n, p, q, A, X1、X2、X3、X4、Y、R1、R2、R3、R4、R5、R6、R9And R10As defined herein.
Flow B
In flow B step 1, according to above with reference to flow A methods describeds, make three-(tert-butyl group)-silicyl epoxide Amine k and arylsulfonyl chloride b reacts, and forms sulfonamide compounds m.In certain embodiments, three-(tert-butyl group)-monosilane oxygen Base can be substituted by other leaving groups.
In step 2, sulfonamide compounds m is reacted with iodine chloromethanes, obtain alkenyl sulfonamide compounds n.The reaction It can be carried out in anhydrous conditions in the presence of highly basic (such as alkyl lithium reagents), using polar proton inert solvent (such as THF). In some embodiments, iodine chloromethanes can be substituted with other methylene reagents.
In step 3, carry out cyclization and obtain oxygen thia cycloheptyl hydride compounds p.The cyclization can be in polarity matter Carried out under the conditions of sub- atent solvent in the presence of amine base.
In step 4, the mode according to above with reference to flow A, by oxygen thia cycloheptyl hydride compounds p and aralkyl halogen Compound compound e reacts, and obtains aralkyl oxy thiazepine cycloheptyl hydride compounds q.
Mode according to above with reference to flow A, step 5A or 5B can pass through oxygen thiazepine cycloheptyl hydride compounds q Reacted respectively with reagent g and i, respectively obtain sultam compound r and s, it is compound of formula I of the invention.
Flow A and flow B method can be variously changed, this can provide suggestion to those skilled in the art. The detail for preparing the compounds of this invention is described in the following embodiments.
Administration and Pharmaceutical composition
The present invention includes Pharmaceutical composition, and the Pharmaceutical composition includes at least one compound of the invention or its is single Isomers, the racemic of isomers or non-racemic mixture or pharmaceutically useful salt or solvate and at least one are pharmaceutically useful Carrier and optional other treatments and/or prevention composition.
In general, the compounds of this invention is by can by any of the medicine for playing similar applications with therapeutically effective amount The administering mode administration of receiving.Appropriate dosage range is usually daily 1-500mg, such as daily 1-100mg, most preferably often Day 1-30mg, this depends on many factors, such as the order of severity of disease to be treated, individual age and relative health, The targeted indication of the effect of compound used therefor, method of administration and form, administration and the preference and experience of related doctor.Control Those of ordinary skill in the art of such disease are treated without excessive experiment, by personal knowledge and present disclosure just It can determine that therapeutically effective amount of the compounds of this invention for given disease.
The compounds of this invention can be used as pharmaceutical preparation to apply, including suitable for oral (including oral cavity and sublingual), rectum, Nasal cavity, part, lung, the preparation of vagina or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) or with suitable Together in the form by sucking or being blown into administration.The concrete mode of administration is usually to be given using the oral of convenient daily dose scheme Medicine, it can be adjusted according to extent.
The compounds of this invention and one or more customary adjuvants, carrier or diluent can together be made Pharmaceutical composition and The form of unit dose.Pharmaceutical composition and unit dosage forms can be made up of the conventional ingredient of conventional ratio, be contained or not contain Other reactive compound or composition, unit dosage forms can contain the active component of any appropriate effective dose, with the expection used Daily dosage scope is suitable.Pharmaceutical composition can use in solid form, for example, tablet or filling capsule, semisolid, powder, Sustained release preparation or liquid, such as solution, supensoid agent, emulsion, elixir or the filling capsule being administered orally；Or for for straight The suppository form of intestines or vagina administration；Or parenteral uses in the form of aseptic injectable solution.Therefore, appropriate typical flat Formulation is the every preparation containing about 1 milligram of active component, or broadly, containing about 0.01 to about 100 milligram of activity into Point.
The compound of the present invention can be configured to a variety of oral administered dosage forms.Pharmaceutical composition and formulation can include this hair Bright compound or its pharmaceutically useful salt are as active component.Pharmaceutically useful carrier can be solid or liquid.The system of solid form Agent includes pulvis, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be a kind of or more Kind material, it also is used as diluent, flavouring, solubilizer, lubricant, suspending agent, adhesive, preservative, tablet disintegrant Or encapsulating material.In pulvis, the solid of carrier typically micronizing, its active component composition mixture with micronizing. In tablet, active component generally mixes and is pressed into required shape in the proper ratio with the carrier with necessary adhesive power And size.Pulvis and tablet can contain the reactive compound of about 1 to about 70%.Appropriate carrier includes but is not limited to carbonic acid Magnesium, magnesium stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, bassora gum, methylcellulose, carboxymethyl cellulose Plain sodium, low melt wax, cocoa butter etc..Terms " formulation " should include the preparation that reactive compound is used as the encapsulating material of carrier Preparation, there is provided wherein contain or not contain the capsule that the active component of carrier is surrounded by carrier in connection.Equally, also Including cachet and lozenge.Tablet, powder, capsule, pill, cachet and lozenge can be adapted for the solid shape being administered orally Formula.
Include the preparation of liquid form suitable for the other forms of oral administration, including it is emulsion, syrup, elixir, water-soluble Liquor, aqueous suspension, or the Solid form preparations of liquid form preparation can be converted into using eve.Emulsion can be with Prepare in the solution, such as in aqueous solution of propylene glycol, or emulsifying agent can be contained, such as lecithin, anhydro sorbitol list Oleate or Arabic gum.Aqueous pharmaceutical can be by soluble in water and add appropriate colouring agent, flavor enhancement, steady by active component Determine agent and be prepared by thickener.Can be (such as natural or synthetic containing cohesive material by the way that the active component of micronizing is dispersed in Glue class, resin, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents) water in prepare it is water-based mixed Suspension.Solid form preparations include solution, supensoid agent and emulsion, in addition to the active ingredient (s, can also contain colouring agent, flavoring Agent, stabilizer, buffer, artificial and natural sweetener, dispersant, thickener, solubilizer etc..
The compound of the present invention can be formulated for parenteral (such as by drug administration by injection, for example, bolus or Continuous infusion), ampoule, pre-filled syringe, low capacity transfusion device or addition preservative can be present in a unit Multi-dose container.Composition can be supensoid agent, solution or emulsion form in oiliness or aqueous carrier, such as poly- Solution in glycol water.Oiliness or non-aqueous carrier, diluent, the example of solvent or excipient include propane diols, The organic ester (such as ethyl oleate) of polyethylene glycol, vegetable oil (such as olive oil) and injectable, it can include and prepare composition, such as Preservative, wetting agent, emulsifying agent or suspending agent, stabilizer and/or dispersant.Or active component can be powder type, lead to Cross sterile separation sterile solid or obtained by the way that solution is lyophilized, entered using preceding using appropriate carrier such as aseptic apirogen water Row structure.
The compound of the present invention can be configured to ointment, cream or lotion, or transdermal patch, for local application To epidermis.For example, ointment and emulsifiable paste can use water-based or oleaginous base to prepare, and add appropriate thickener and/or gelling Agent.Lotion can be prepared with water-based or oleaginous base, generally also containing one or more emulsifying agents, stabilizer, dispersant, suspending Agent, thickener or colouring agent.It is included in flavored base (usually sucrose and Arabic gum suitable for the preparation of oral cavity local medication Or bassora gum) in include the lozenge of active component；Included in inert base (such as gelatin and glycerine or sucrose and Arabic gum) The lozenge of active component；With the mouthwash that active component is included in appropriate liquid-carrier.
The compounds of this invention can be configured to suppository administration.Low melt wax, such as fatty glyceride or cocoa are melted first The mixture of fat, make active component dispersed for example, by stirring.Then the homogeneous mixture of melting is poured into suitable size Mould in, be allowed to cool and solidify.
The compounds of this invention can be formulated for vagina administration.Also contain carrier known in the art in addition to active component Pessary, tampon, cream, gel, paste, foaming agent or spray be suitable.
Target compound can be formulated for nasal-cavity administration.Solution or supensoid agent can directly be applied by conventional meanses To nasal cavity, such as with dropper, pipette or sprayer.Preparation can be provided with single dose or multiple dose form.In dropper or shifting Under the latter event of liquid pipe, it can apply solution or the suspension of appropriate predetermined to realize by patient.Spraying In the case of day with fog, this can be realized for example, by metering atomising atomizing pump.
The compounds of this invention can be formulated for aerosol administration, particularly respiratory tract and including intranasal administration.The chemical combination Thing generally has e.g., from about 5 microns or smaller of granularity.Such granularity can be obtained by manner known in the art, such as Pass through micronizing.Active component provides in pressurized package with together with appropriate propellant, the propellant such as CFC (CFC) (such as dicholorodifluoromethane, Arcton 11 or dichlorotetra-fluoroethane) or carbon dioxide or other appropriate gases.Gas is molten Glue can also easily include surfactant, such as lecithin.The dosage of medicine can be controlled by metering valve.It is or living Property composition can provide in dry powder form, such as mixture of powders of the compound in appropriate powdered substrate, and powdered substrate is such as Lactose, starch, starch derivatives such as hydroxypropyl methyl cellulose and polyvinylpyrrolidone (PVP).Dust carrier can be in nose Gel is formed in chamber.Powder composition can in units of dosage form, such as the capsule of gelatin or short column or blister package shape Formula, powder can be therefrom administered by inhalator.
When needed, preparation can use prepares suitable for the sustained release of active component or the enteric coating of controlled release drug administration.For example, The compounds of this invention can be prepared in transdermal or subcutaneous delivery device.When need sustained release compound and when patient to controlling When the compliance for the treatment of scheme is most important, these delivery systems are favourable.Compound in transdermal delivery is generally adhered to On the solid support with Skin adhesion.Target compound can also combine with penetration enhancers, such as azone (1- ten Dialkyl group azacyclo- hept- 2- ketone).Sustained release transmission system is subcutaneously implanted hypodermic layer by performing the operation or injecting.It is subcutaneously implanted Compound is encapsulated in fat-soluble film (such as silicon rubber) or biodegradable polymer (such as PLA) by thing.
Pharmaceutical preparation can be unit dosage forms.In this form, preparation is subdivided into the list containing appropriate active component Position dosage.Unit dosage forms can be the preparation of packaging, and the packaging includes the preparation of discontinuous quantity, such as the tablet of packaging, capsule And the pulvis in bottle or ampoule.Equally, unit dosage forms can be capsule, tablet, cachet or lozenge in itself, or it can To be these an appropriate number of any formulations of packaged form.
Other appropriate pharmaceutical carriers and their preparation are described in Remington：The Science and Practice of Pharmacy (formulation science and put into practice) 1995, E.W.Martin is edited, Mack Publishing Company, the 19th edition, Easton, Pennsylvania.Representative drugs preparation comprising the compounds of this invention is described as follows.
Purposes
The compounds of this invention is generally used for treating immunological diseases.The compound can be used for treatment of arthritis, including class wind Wet arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathy, urarthritis, systematicness Lupus erythematosus and juvenile arthritis, osteoarthritis and other arhritis conditions.
The compound can be used for treating respiratory disease, such as chronic obstructive pulmonary disease (COPD), asthma, bronchus convulsion Contraction etc..
The compound can be used for treating gastrointestinal disease, such as IBS (IBS), inflammatory bowel disease (IBD), and courage twists Pain and other disease of biliary tract, renal colic, diarrhoea-dominant IBS, the pain related to GI expansions etc..
The compound can be used for treating antalgesic, such as inflammatory pain；Arthritis ache, surgical pain；Splanchnodynia； Toothache；Premenstrual pain；Central pain；Pain caused by burn；Antimigraine or cluster headache；Neurotrosis；Neuritis；God Dysmenorrhoea；Poisoning；Ischemia injury；Interstitial cystitis；Cancer pain；Virus, parasite or bacterium infection；Post traumatic injuries； Or the pain related to IBS.
General experimental
LCMS methods：
One of following method is used to carry out High Performance Liquid Chromatography/Mass Spectrometry (LCMS) experiment to determine retention time (RT) and phase Close mass ion：
Method A：Using following condition analysis compound：Be connected to be equipped with UV PDADs and 100 from Tested on the mono- QMSs of Waters ZMD of the Hewlett-Packard HP1100LC systems of dynamic injector.Spectrum Instrument has the electrospray ionization source run with cation and negative ion mode.The system makes under environment temperature and 2.0mL/min flow velocitys With 3 μm of C18 of Phenomenex Luna (2), 30 × 4.6mm posts.Initial solvent system is above 0.5 minute to contain 0.1% 95% water (solvent orange 2 A) of formic acid and 5% acetonitrile (solvent B) containing 0.1% formic acid, subsequent 4 minutes gradients to 5% solvent orange 2 A and 95% solvent B.Kept for 1 minute, 95% solvent orange 2 A and 5% solvent B were then back in 0.5 minute.Total run time is 6 points Clock.
Method B：Using following condition analysis compound：It is being connected to the Waters Acquity of outfit PDA UV detectors Tested on the Waters Micromass ZQ2000 QMSs of UPLC systems.Spectrometer has with cation and born The electrospray ionization source of ion mode operation.The system uses the 1.7 μm of 100 × 2.1mm of Acquity BEH C18 for being held in 40 DEG C Post or the Acquity BEH Shield 1.7 μm of 100 × 2.1mm posts of RP18 for being held in 40 DEG C and 0.4mL/min flow velocitys.Just Beginning solvent system is above 95% water (solvent orange 2 A) containing 0.1% formic acid of 0.4 minute and 5% acetonitrile containing 0.1% formic acid (solvent B), subsequent 5.6 minutes gradients to 5% solvent orange 2 A and 95% solvent B.Kept for 0.8 minute, then returned in 1.2 minutes To 95% solvent orange 2 A and 5% solvent B.Total run time is 8 minutes.
Method C：Using following condition analysis compound：It is being connected to the Waters Acquity of outfit PDA UV detectors Tested on the Waters ZMD mass spectrographs of UPLC systems.Spectrometer has the EFI run with cation and negative ion mode Mist source.The system uses the 1.7 μm of 50 × 2.1mm posts of Acquity CSH C18 for being held in 40 DEG C and 1.0mL/min flow velocitys. Initial solvent system is 97% water (solvent orange 2 A) containing 0.1% formic acid and 3% containing 0.1% formic acid of above 0.15 minute Acetonitrile (solvent B), subsequent 1.85 minutes gradients to 1% solvent orange 2 A and 99% solvent B.Kept for 0.4 minute, then in 0.1 minute It is back to 97% solvent orange 2 A and 3% solvent B.Total run time is 2.5 minutes.
NMR methods：
1H H NMR spectroscopies are recorded using one of following equipment in environment temperature or at 80 DEG C：It is equipped with triple resonant 5mm probes Varian Unity Inova (400MHz) spectrometer, be equipped with triple resonant 5mm probes Bruker Avance DRX 400 (400MHz) spectrometer, detected with being ready for use on1H and13The Bruker Avance DPX 300 of C standard 5mm bifrequency probes (300MHz), outfit standard 5mm1H/13The Bruker FouRier 300MHz systems of C probes, using BBI Broad B and The Bruker AVIII (400MHz) of the Inverse 5mm probes or Bruker AVIII using QNP (four nuclear detection) 5mm probes (500MHz).Chemical shift is represented with the ppm relative to internal standard tetramethylsilane (ppm=0.00).Using following abbreviation：Br= Bandwidth signals, s=is unimodal, and d=is bimodal, and dd=double doublets, t=triplets, td=is triple bimodal, and dddd=is dual dual double Weight peak, q=quartets, m=multiplets, or its any combinations.
Microwave reactor：
Microwave reaction usesCarry out, react in the bottle being adapted with reaction scale Temperature and time is described in experimental detail.
Purifier apparatus：
Purifying is using pre-filled silicagel column in Teledyne ISCOOrIsoleraUpper progress, or compressed air is used to apply external pressure.Using the solvent and gradient shown in experimental detail.
The compound specified using RPLC (HPLC) purifying.Separation is as stationary phase Carried out on Phenomenex Gemini C18 posts (250 × 21.2mm, 5micron) using gradient elution, using the flowing specified Phase, carried out with 18mL/min flow velocity, it is automatic using Gilson UV/Vis-155 double-channel detectors and Gilson GX-271 Liquid processor.
Phase separator post byWithPhase separator post is supplied.
(directed) instructed using mass spectrum the compounds that purifying (MDAP) purifying is specified automatically.Using Agilent 1260Infinity purification systems separate, and 5 μm of XSelect CSH Prep C18,21 × 250mm is as stationary phase, in room temperature Lower holding, flow velocity 19mL/min.Initial solvent system is 90% water (solvent orange 2 A) containing 0.1% formic acid and containing 0.1% first 10% acetonitrile (solvent B) of acid, subsequent gradient to 5% solvent orange 2 A and 95% solvent B, around a specific emphasis gradient (a Specific focused gradient), more than 22 minutes.Started by the single quadrupole LC/MS systems of the series of Agilent 6100 Product is collected.Unless otherwise indicated, by required component in 40 DEG C of vacuum concentrations, by residue in MeCN- water (1:1) freezing is dry in It is dry.
Abbreviated list
AcOH acetic acid
AIBN 2,2 '-azo two (2- methyl propionitrile)
Aq. it is water-based
Atm. atmospheric pressure
BOC tert-butyl Epoxide carbonyls
(BOC)2The carbonic acid di-tert-butyl esters of O bis-
CrO3Chromium oxide (VI)
CDCl3Deuterated chloroform
DavePhos 2- dicyclohexyls phosphino- -2 '-(N, N- dimethylamino) biphenyl
DCM dichloro-s methane/METHYLENE CHLORIDE
DMA DMAC N,N' dimethyl acetamides
DIAD azoformic acid two-i-propyl esters
Bis--wopropyl ethyl amines of DIPEA
DMAP 4-dimethylaminopyridines
DME 1,2- dimethoxy-ethanes
DMF N,N-dimethylformamides
DMSO dimethyl sulfoxide (DMSO)s
DPPF 1,1'- bis- (diphenylphosphino) ferrocene
ES electron sprays
Et2O ether
Et3N triethylamines
EtOH ethanol/ethyl alcohol
EtOAc ethyl acetate
H2O water
H2SO4Sulfuric acid
HATU 2- (1H-7- azepine benzos triazol-1-yl) -1,1,3,3- tetramethylurea hexafluorophosphate first ammoniums
(methanamimium)
HBTU O- BTA -1- bases-N, N, N ', N '-tetramethylurea hexafluorophosphate
HCO2H formic acid
HCl hydrochloric acid
HOBT I-hydroxybenzotriazoles
HPLC high performance liquid chromatography
RP HPLC RPLCs
IBX 2- iodoso benzoic acid
Alcohol (spirit) industrial methylated IMS
KOH potassium hydroxide
K2CO3Potassium carbonate
LDA lithium diisopropylamides
I-PrOH isopropanols/isopropyl alcohol/propan-2-ol
LCMS liquid chromatography/mass spectrometries
LiOH lithium hydroxides
The automatic purifying elution (preparative LCMS) of MDAP mass-guidance
MgSO4Magnesium sulfate
MeOH methanol/methylol
MW microwaves
NaH sodium hydrides
NaCl sodium chloride
NaOH sodium hydroxides
Na2SO4Sodium sulphate
Na2CO3Sodium carbonate
NaHCO3Sodium acid carbonate
NBS N-bromosuccinimides
NH4Cl ammonium chlorides
NMP 1-Methyl-2-Pyrrolidones
POCl3POCl3
PhCH3Toluene
Pd2(dba)3Three (dibenzylidene benzylacetone) two palladiums (0)
PSI PSIs
RT room temperatures
Sat. saturation
SCX-2 has the pre-filled of chemical bonding propane sulfonic acid functional groupSilica-based adsorbent
SFC supercritical fluid chiral chromatograms
TBDMS tert-butyl dimetylsilyls
TFA trifluoroacetic acids
THF tetrahydrofurans
TIPS triisopropylsilyls
TLC thin-layer chromatographys
XantPhos 4,5- bis- (diphenylphosphino) -9,9- dimethyl xanthenes
Prepare 1 and 2：(3R) -3- amino butyl- 1- alcohol and (3S) -3- amino butyl- 1- alcohol
Step 1 3- [[(benzyl epoxide) carbonyl] amino] butyric acid
The water of 3- aminobutyric acids (100g, 969.75mmol, 1.00equiv) is added into 2000mL 4- neck round-bottom flasks (1000mL) solution, potassium hydroxide (136g, 2.42mol, 2.50equiv) is then added portionwise.Under 0-5 DEG C, stirring, to Benzyl chloroformate (247g, 1.45mol, 1.50equiv) is wherein added dropwise.The solution of acquisition is stirred into 5h in 25 DEG C.Pass through LCMS monitors reaction process.The solution of acquisition is extracted with dichloromethane, combining water layer.Using hydrochloric acid (2mol/L) by the pH of aqueous phase Value is adjusted to 3.Sediment is collected by filtration, dries, obtains 102g (44%) 3- [[(benzyl epoxide) carbonyl] amino] butyric acid, is White solid.
Step 2：N- [(2S) -4- hydroxyl butyl- 2- yls] carbamic acid benzyl esters and N- [(2R) -4- hydroxyl butyl- 2- yls] ammonia Base benzyl chloroformate
Nitrogen is filled with to 2000mL 3- neck round-bottom flasks and keeps inert environments, adds 3- [[(benzyl epoxide) carbonyl] ammonia Base] butyric acid (102g, 429.92mmol, 1.00equiv) THF (300mL) solution, with after 0-5 DEG C, stirring is lower is added dropwise BH3/THF(1N)(645mL,1.50equiv).The solution of acquisition is stirred into 2h in 40 DEG C, is quenched by adding 200mL methanol, It is concentrated in vacuo.Residue is purified on a silica gel column, uses ethyl acetate:Petroleum ether (1:2) elute.Crude material (70g) passes through Prep-SFC is purified, using following condition (prep SFC)：Post, Phenomenex Lux 5u Cellulose-4,2.12*25, 5um；Mobile phase, CO2(85%), ethanol (15%)；Detector, UV 254nm.Obtain the 30g (31.5%) for pale solid N- [(2R) -4- hydroxyl butyl- 2- yls] carbamic acid benzyl esters and for pale solid 30g (31.5%) N- [(2S) -4- Hydroxyl butyl- 2- yls] carbamic acid benzyl ester.
Step 3：(3R) -3- amino butyl- 1- alcohol and (3S) -3- amino butyl- 1- alcohol
Into 1000mL round-bottomed flasks add N- [(2S) -4- hydroxyl butyl- 2- yls] carbamic acid benzyl ester (30g, 134.4mmol, 1.00equiv) methanol (500mL) solution and palladium charcoal (3g, 0.10equiv).By the solution of acquisition in 25 DEG C, 12h is stirred under hydrogen environment.Filter solid is crossed, is concentrated in vacuo filtrate, obtains 11.7g (92%) (3S) -3- amino butyl- 1- alcohol, For grease.1H NMR(300MHz,DMSO,ppm)：δ4.48(3H,s),3.47(2H,s),2.96(1H,s),1.47-1.41 (2H,q),1.02-0.99(3H,d)；LCMS(ESI),m/z,90[M+H]+；Measured value [α]D 20.2+ 11.65 ° of (C=1.22g/ 100mL is in EtOH), literature value [α]D 20+ 16.3 ° (c=4.5 is in EtOH) (J.Org.Chem.1996,61,2293- 2304.)。
Using the above method, separation obtains 12.0g 12g (94%) (3R) -3- amino butyl- 1- alcohol, is grease.1H NMR(300MHz,DMSO,ppm)：δ4.48(3H,s),3.47(2H,s),2.96(1H,s),1.47-1.41(2H,q),1.02- 0.99(3H,d)；LCMS(ESI),m/z,90[M+H]+；Measured value [α]D 20.2- 11.1 ° (C=0.32g/100mL is in EtOH), Literature value [α]D 25- 25 ° of (c=1.25 is in EtOH) (Tetrahedron：Asymmetry 1999,10,2213–2224.).
Prepare 3：(R)-N- (4- chloro butyl- 2- yls) -1- phenyl methanesulfonamide acid amides
Step 1：(R) -3- (Phenylmethylsulfonyl amino) butyl phenyl methanesulfonates
In 0 DEG C, to the four of (3R) -3- amino butyl- 1- alcohol (1.0g, 11.2mmol) and triethylamine (3.3mL, 23.6mmol) Phenyl methanesulfonamide acyl chlorides (4.49g, 23.6mmol) is slowly added in hydrogen furans (37mL) solution, reactant is stirred 16 at room temperature Hour.Then MTBE (100mL) is added, Et is removed by filtration3NHCl salt.Then filtrate is concentrated, obtains crude product (R) -3- (Phenylmethylsulfonyl amino) butyl phenyl methanesulfonates, it can directly be used without purifying.LCMS(ESI),m/z,398[M +H]+。
Step 2：(R)-N- (4- chloro butyl- 2- yls) -1- phenyl methanesulfonamide acid amides
Sodium chloride is added into crude product (R) -3- (Phenylmethylsulfonyl amino) butyl phenyl methanesulfonates (23.6mmol) (984mg, 16.8mmol) and dimethylformamide (37mL), reactant is stirred 16 hours in 80 DEG C.Then reactant is used EtOAc dilute, it is dried over magnesium sulfate with water (× 2) and salt water washing, concentrate, by silica gel chromatography (0-50%'s Acetone n-heptane solution, 216nM), acquisition (R)-N- (4- chloro butyl- 2- yls) -1- phenyl methanesulfonamides acid amides (1.71g, 6.53mmol, Two step yields 58%).LCMS(ESI),m/z,261[M+H]+.
The other compounds prepared using the above method are as shown in table 1.
Table 1
Prepare 7：N- (2- bromoethyls) (phenyl) Methanesulfomide
In 0 DEG C, by K2CO3(8.7g, 62mmol) adds to phenyl methanesulfonamide acyl chlorides (6g, 31mmol) and 2- bromine ethamine hydrobromic acids In DCM (100mL) mixture of salt (6.4g, 31mmol).The mixture of acquisition is stirred 4 hours at room temperature, stood overnight. When the reactions are completed, water (100mL) is added, separates DCM phases.Aqueous phase is extracted using DCM.The organic phase of merging is done through sodium sulphate It is dry, filter and be concentrated in vacuo, obtain crude product, used pillar layer separation (silica gel of 200-300 mesh, 0-50% EtOAc Petroleum ether solution), compound N-(2- bromoethyls) (phenyl) Methanesulfomide (7.0g, 80%) is obtained, is faint yellow solid.1H NMR(300MHz,CDCl3)δ7.40(m,5H),4.58(m,1H),4.29(s,2H),3.34-3.29(m,4H)。LCMS(ESI), 300,302[M+Na]+, find Br collection of illustrative plates.
Prepare 8：N- (2- bromoethyls) (4- fluorophenyls) Methanesulfomide
N- (2- bromoethyls) (4- fluorophenyls) Methanesulfomide is prepared using the above method, using 4- fluoro-phenyl mesyl chlorides Instead of phenyl methanesulfonamide acyl chlorides.1H NMR(300MHz,CDCl3)δ7.43-7.38(m,2H),7.13-7.07(m,2H),4.62(br s,1H),4.26(s,2H),3.41-3.32(m,4H)。
Prepare 9：N- (3- bromopropyls) (phenyl) Methanesulfomide
In 0 DEG C by phenyl methanesulfonamide solution of acid chloride (2.19g, 10mmol) add to 3- bromine propyl- 1- amine hydrobromate (2.19g, 10mmol) and Et3In N (2.02g, 20mmol) THF (50mL) suspension.Mixture is stirred into 5min in 0 DEG C.TLC confirms Reaction is completed.Solid is filtered by suction, filtrate concentrates, acquisition compound N-(3- bromopropyls) (phenyl) Methanesulfomide (2.7g, Quant.), it is faint yellow solid, it need not be further purified and be used directly for next step.1H NMR(300MHz,CDCl3) δ 7.40 (m, 5H), 4.48 (m, 1H), 4.27 (s, 2H), 3.41 (t, J=6.6Hz, 2H), 3.16 (q, 2H), 2.01 (m, 2H). LCMS (ESI), m/z, 314 and 316 [M+Na]+, find Br collection of illustrative plates.
Prepare 10：N- (3- bromopropyls) (4- fluorophenyls) Methanesulfomide
N- (3- bromopropyls) (4- fluorophenyls) Methanesulfomide is prepared using the above method.1H NMR(300MHz,CDCl3)δ 7.42-7.37(m,2H),7.13-7.07(m,2H),4.26(m,1H),4.24(s,2H),3.46-3.42(m,2H),3.20- 3.16(m,2H),2.05-2.00(m,2H)。
Prepare 11：6- phenyl -1,2- thiazan 1,1- dioxide
In -78 DEG C to N- (3- bromopropyls) -1- phenyl methanesulfonamides acid amides (2.3g, 7.9mmol), diisopropylamine (0.28mL, N-BuLi 2.0mmol) and in tetrahydrofuran (26mL) solution of 1,10- phenanthrolenes (3.6mg, 0.02mmol) is added dropwise (6.8mL, 2.5M hexane solution), reactant is stirred 16 hours.Then the NH of saturation is added4Cl, reactant are dilute with EtOAc Release, dried over magnesium sulfate with water and salt water washing, concentration, by silica gel chromatography (0-50% EtOAc/ heptane), Obtain 6- phenyl -1,2- thiazan 1,1- dioxide (1.3g, 80% yield).1H NMR(300MHz,DMSO-d6)δ 7.40-7.35(m,5H),6.98(m,1H),4.12(dd,1H),3.26-3.20(m,2H),2.40-2.30(m,1H),2.16- 2.12(m,1H),1.77-1.65(m,2H)。LCMS(ESI),m/z,234[M+Na]+(reference：D.Askin, etc. Org.Lett.2003,4175.)
The other compounds prepared using above-mentioned steps are as shown in table 2.
Table 2
Prepare 19：3- phenyl -1,4,5- oxygen sulfur nitrogen heterocycle heptane 4,4- dioxide
Step 1：N- (2- ((tert-butyl dimetylsilyl) epoxide) ethyl) -1- phenyl methanesulfonamide acid amides
In 0 DEG C to 2- ((tert-butyl dimetylsilyl) epoxide) ethamine (11.7g, 66.6mmol) and triethylamine Be slowly added to by several times in tetrahydrofuran (222mL) solution of (11.2mL, 79.9mmol) phenyl methanesulfonamide acyl chlorides (12.7g, 66.6mmol), reactant is stirred at room temperature 16 hours.Then MTBE is added, is filtered to remove Et3NHCl salt.By filtrate Concentration, by silica gel chromatography (0-30% acetone n-heptane solution, 216nM), obtain N- (2- ((tert-butyl dimethyl Silicyl) epoxide) ethyl) -1- phenyl methanesulfonamides acid amides (17.8g, 81% yield).LCMS(ESI),m/z,330.[M+H] +。
Step 2：N- (2- ((tert-butyl dimetylsilyl) epoxide) ethyl) -1- phenyl ethyl sulfonamides
In -78 DEG C to N- [2- [tert-butyl (dimethyl) silicyl] epoxide ethyl] -1- phenyl-methane-sulfonamides (33g, N-BuLi (2.5M hexane solution) is slowly added to by conduit in tetrahydrofuran (334mL) solution 100.2mmol) (100mL, 250mmol), reactant is stirred 2 hours in -78 DEG C.Be then slowly added into chloro iodomethane (8.3mL, 110mmol), reactant is stirred 1 hour in -78 DEG C, then warmed to room temperature, aging 16 hours.Then reactant is used full The NH of sum4Cl be quenched, extracted with dichloromethane, it is dried over magnesium sulfate, concentration, by silica gel chromatography (0-60%'s EtOAc n-heptane solutions), obtain N- [2- [tert-butyl (dimethyl) silicyl] epoxide ethyl] -1- phenyl-ethyl sulfonamide (24g, 70% yield).LCMS(ESI),m/z,342.[M+H]+.
Step 3：3- phenyl -1,4,5- oxygen sulfur nitrogen heterocycle heptane 4,4- dioxide
In 0 DEG C to N- (2- ((tert-butyl dimetylsilyl) epoxide) ethyl) -1- phenyl ethyl sulfonamide (717mg, Tetrabutyl ammonium fluoride (1.0M THF solution) (2.2mL, 2.2mmol) is added dropwise in tetrahydrofuran (7mL) solution 2.1mmol), Reactant is stirred at room temperature 16 hours.Then the NH of saturation is added4Cl, product extracts (× 2) with dichloromethane, through sulfuric acid Magnesium is dried, concentration, by silica gel chromatography (0-100% EtOAc n-heptane solutions), obtains 3- phenyl-Isosorbide-5-Nitrae, 5- oxygen sulphur Azepan 4,4- dioxide (401mg, 84% yield).(24g, 70% yield).LCMS(ESI),m/z,228. [M+H]+.(reference：P.Hansen etc., Org.Lett.2008,2951).
The other compounds prepared using above-mentioned steps are as shown in table 3.
Table 3
Embodiment 1：(3S, 6R) -2- [[bis- fluoro- 4- of 2,5- [3- [(5- methyl-isoxazole -3- bases) methoxyl group] oxa- ring fourths Alkane -3- bases] phenyl] methyl] -3- methyl -6- phenyl-thiazan 1,1- dioxide
Step 1：3- (the bromo- 2,5- difluorophenyls of 4-)-oxetanes -3- alcohol
In in -30 DEG C, 5 minutes to stirring bromo- 2, the 5- difluoros iodobenzenes (5.0g, 15.7mmol) of 4- anhydrous THF Isopropylmagnesium chloride (10.2mL, 20.4mmol, 2.0M THF solution) is added in (45mL) solution.Oxa- ring fourth is added dropwise after 1h Anhydrous THF (20mL) solution of alkane -3- ketone (1.47g, 20.4mmol), stirs 0.5h by reactant, then warms to room temperature. After 16h, by the NH of reactant saturation4The Cl aqueous solution (30mL) is quenched, and is extracted with EtOAc, dried over sodium sulfate and vacuum is dense Contracting.By purification by flash chromatography (0-80% EtOAc/ hexamethylenes), target compound is obtained, is pale yellow oil (2.65g)。1H NMR(300MHz,CDCl3) δ 7.35 (1H, dd, J=5.4,9.6Hz), 7.17 (1H, dd, J=6.6, 8.4Hz),5.11-5.06(2H,m),4.85-4.79(2H,m),3.25(1H,s)。
Step 2：3- pi-allyl epoxides -3- (the bromo- 2,5- difluorophenyls of 4-)-oxetanes
In 0 DEG C of 3- (the bromo- 2,5- difluorophenyls of 4-)-oxetanes -3- alcohol (2.00g, 7.55mmol) to stirring Sodium hydride (453mg, 11.3mmol 60% dispersion oil) is added in anhydrous DMA (22mL) solution by several times.By reactant 0.5h is stirred, allyl bromide, bromoallylene (0.973mL, 11.3mmol) is then added, reactant is stirred into 1h at room temperature.Reactant is used Salt solution is quenched (30mL), is extracted with EtOAc, dried over sodium sulfate and be concentrated in vacuo.By purification by flash chromatography (0-80%'s EtOAc/ hexamethylenes), obtain the target compound (2.12g) for grease.1H NMR(300MHz,CDCl3)δ7.34(1H,dd, ), J=5.7,9.3Hz 7.02 (1H, dd, J=6.3,8.4Hz), 5.87 (1H, ddt, J=5.4,10.2,17.3Hz), 5.27 (1H, dq, J=1.5,17.3Hz), 5.16 (1H, dq, J=1.5,10.2Hz), 5.00-4.90 (4H, m), 3.83-3.77 (2H, m)。
Step 3：4- (3- pi-allyls epoxide-oxetanes -3- bases) -2,5- difluoro-benzaldehydes
In -78 DEG C to stirring 3- pi-allyl epoxides -3- (the bromo- 2,5- difluorophenyls of 4-)-oxetanes (2.12g, N- butyl lithiums (6.50mL, 10.4mmol, 1.6M hexane solution) are added dropwise in anhydrous THF (55mL) solution 6.95mmol).Will Reactant stirs 0.5h, then adds dry DMF (2.25mL, 27.8mmol), warms to room temperature reactant after 0.5h.After 1h By the NH of reactant saturation4The Cl aqueous solution (30mL) is quenched, and is extracted with EtOAc, dried over sodium sulfate and be concentrated in vacuo.
Step 4：[4- (3- pi-allyls epoxide-oxetanes -3- bases) -2,5- difluorophenyls]-methanol
The residue that will be obtained from step 3 is dissolved in MeOH (35mL), is cooled to 0 DEG C, add by several times sodium borohydride (1.05mg, 27.8mmol).By reactant H after 0.5h2O (20mL) is quenched, and is extracted with EtOAc, the extract salt water washing of merging, is passed through Sodium sulphate is dry and is concentrated in vacuo.By purification by flash chromatography (0-80% EtOAc/ hexamethylenes), the mesh for grease is obtained Mark compound (900mg).1H NMR(300MHz,CDCl3) δ 7.23 (1H, dd, J=5.7,10.2), 6.92 (1H, dd, J= ), 6.0,9.6Hz 5.87 (1H, ddt, J=5.4,10.2,17.3Hz), 5.27 (1H, dq, J=1.5,17.3Hz), 5.16 (1H, Dq, J=1.5,10.2Hz), 5.03-4.90 (4H, m), 4.77 (2H, d, J=5.7Hz), 3.82-3.76 (2H, m), 1.87 (1H, t, J=6.0Hz).
Step 5：Methanesulfonic acid 4- (3- pi-allyls epoxide-oxetanes -3- bases) -2,5- difluoro-benzyls
In 0 DEG C of [4- (3- pi-allyls epoxide-oxetanes -3- bases) -2,5- difluorophenyls]-methanol to stirring Mesyl chloride (0.347mL, 4.57mmol) is added in DCM (35mL) solution of (900mg, 3.51mmol), then adds three second Amine (0.732mL, 5.27mmol).After 1h, reactant is concentrated in vacuo, residue is filtered by phase separator, using quick color Spectrum purifying (0-70% EtOAc/ hexamethylenes), obtains the target compound (927mg) for grease.1H NMR(300MHz, CDCl3) δ 7.23 (1H, dd, J=5.7,9.6Hz), 7.01 (1H, dd, J=6.0,9.6Hz), 5.87 (1H, ddt, J=5.4, ), 10.5,17.3Hz 5.32-5.23 (3H, m), 5.16 (1H, dq, J=1.5,10.5Hz), 5.03-4.91 (4H, m), 3.84- 3.78(2H,m),3.07(3H,s)。
Step 6：(3S, 6R) -2- [4- (3- pi-allyls epoxide-oxetanes -3- bases) -2,5- diiluoro-benzyls] -3- first Base -6- phenyl-[1,2] thiazan 1,1- dioxide
It will be obtained from product (871mg, 2.61mmol), the Cs of step 52CO3(1.28g, 3.92mmol), DMA (5mL) and The mixture stirring 4h of (3S, 6R) -3- methyl -6- phenyl-thiazan 1,1- dioxide (528mg, 2.34mmol).Will reaction Thing H2O is quenched, and is extracted with EtOAc, dried over magnesium sulfate and be concentrated in vacuo.By crystallization purifying (EtOAc- heptane), obtain Target compound (950mg).
Step 7：3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazine Alkane -2- ylmethyls)-phenyl]-oxetanes -3- alcohol
It will be obtained from the product (100mg, 0.216mmol), triphenylphosphine (23mg, 0.02mmol) and K of step 62CO3 The mixture of (13mg, 0.82mmol) in EtOH (5mL) is heated at reflux 0.5h.By reactant H2O is quenched, and is extracted with EtOAc Take, it is dried over magnesium sulfate and be concentrated in vacuo.Pass through purification by flash chromatography (1:1EtOAc/ hexamethylenes) and crystallize (EtOAc- hexamethylenes Alkane), obtain target compound (50mg).1H NMR(400MHz,DMSO-d6)δ7.46-7.20(6H,m),6.44(1H,s), 4.91 (2H, d, J=6.8Hz), 4.63 (2H, d, J=6.9Hz), 4.56-4.47 (2H, m), 4.35 (1H, d, J=17.8Hz), 4.15-4.07(1H,m),2.43-2.37(1H,m),2.11-2.05(1H,m),1.84-1.72(1H,m),1.68-1.60(1H, M), 1.09 (3H, d, J=6.8Hz).LCMS(ESI)：M/z=424.1 [M+H]+。
Step 8：(3S, 6R) -2- [[bis- fluoro- 4- of 2,5- [3- [(5- methyl-isoxazole -3- bases) methoxyl group] oxa- ring fourths Alkane -3- bases] phenyl] methyl] -3- methyl -6- phenyl-thiazan 1,1- dioxide
In 0 DEG C into DMA (3mL) solution of the product (0.4g, 0.95mmol) obtained from step 7 add NaH (40mg, 1.0mmol, 60% dispersion oil).After 0.5h, 3- chloromethyl -5- methyl-isoxazoles are added, reactant is warmed to Room temperature, persistently stir 45min.By reactant H2O is quenched, and is extracted with EtOAc, dried over magnesium sulfate and be concentrated in vacuo.Pass through Purification by flash chromatography (1:2-1:1EtOAc/ hexamethylenes) and crystallize (EtOAc- hexamethylenes), obtain target compound (48mg). LCMS(ESI)：M/z=519.1 [M+H]+。
Embodiment 2：Trans 5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazine Alkane -2- bases] methyl] phenyl] -3- hydroxy-3-methyls-cyclobutyl] -3H-1,3,4- oxadiazole -2- ketone
Step 1：(the fluoro- 4- aminomethyl phenyls of 2,5- bis-) methanol
It is molten to the THF (80mL) of the fluoro- 4- methyl benzoic acids (17.2g, 99.92mmol) of 2,5- bis- in 0 DEG C, 30 minutes Borine-tetrahydrofuran compound (200mL, 200mmol) is added dropwise in liquid, mixture is then heated into 2h in 60 DEG C.By reactant Room temperature is cooled to, reactant is quenched with salt solution.The mixture of acquisition is poured into water, extracted (2 × 100mL) with EtOAc.Merge Organic extract liquid, it is dried over sodium sulfate with salt water washing (2 × 50mL), filter and be concentrated under reduced pressure.Residue passes through silica gel chromatograph Purifying, eluant, eluent is used as using petroleum ether/EtOAc (3/1), target compound is obtained, is white solid.(15.5g, 98% Yield).LCMS(ESI)：M/z=141.2 [M-OH]+。
Step 2：Two fluoro- 4- methylbenzenes of 1- (chloromethyl) -2,5-
By (the fluoro- 4- aminomethyl phenyls of 2,5- bis-) methanol (15.5g, 98.1mmol) in SOCl2Mixture in (60mL) in 12h is stirred at room temperature.Removal of solvent under reduced pressure obtains the crude material (16g, 93% yield) for yellow oil.Crude product chemical combination Thing need not be further purified and be used directly for next step.
Step 3：2- (the fluoro- 4- aminomethyl phenyls of 2,5- bis-) acetonitrile
By two fluoro- 4- methylbenzenes (18g, 102.3mmol) of 1- (chloromethyl) -2,5-, NaCN (30.1g, 613.6mmol) With TBAB (3.29g, 10.2mmol) in DCM/ water (1：Mixture in 1,240mL) stirs 12h at room temperature.Reactant is fallen Enter in water (150mL), extracted (2 × 100mL) with DCM.The extract of merging is done through sodium sulphate with salt water washing (2 × 50mL) It is dry, filter and be concentrated under reduced pressure.Residue is used as eluant, eluent using petroleum ether/EtOAc (3/1), obtained by silica gel chromatography For the target compound of yellow solid.(16.4g, 96% yield).LCMS(ESI)：M/z=168.1 [M+H]+。
Step 4：1- (the fluoro- 4- aminomethyl phenyls of 2,5- bis-) -3,3- dimethoxy cyclobutane formonitrile HCNs
At room temperature, it is molten to the DMSO (200mL) of 2- (2,5- bis- fluoro- 4- aminomethyl phenyls) acetonitrile (16.7g, 100mmol) NaH (8g, 200mmol, 60% oil dispersion liquid) is added in liquid by several times.Reactant is stirred into 1h at room temperature, then adds 1, The bromo- 2,2- dimethoxy propanes (39.3g, 150mmol) of 3- bis-.Reactant is heated into 6h in 60 DEG C.By reactant in 0 DEG C with water (100mL) is quenched, and is extracted (2 × 100mL) with EtOAc.Merge organic extract liquid, with salt water washing (2 × 50mL), through sodium sulphate Dry, filter and be concentrated under reduced pressure.Residue is used as eluant, eluent using petroleum ether/EtOAc (4/1), obtained by silica gel chromatography It must be the target compound (12g, 45% yield) of yellow solid.1H NMR(400MHz,DMSO-d6)δ7.36-7.28(m, 2H), 3.18 (s, 3H), 3.05 (s, 3H), 3.03 (d, J=13.6Hz, 2H), 2.77 (d, J=13.6Hz, 2H), 2.24 (d, J =1.6Hz, 3H).LCMS(ESI)：M/z=268.0 [M+H]+。
Step 5：1- (the fluoro- 4- aminomethyl phenyls of 2,5- bis-) -3,3- dimethoxy cyclobutane formates
By 1- (the fluoro- 4- aminomethyl phenyls of 2,5- bis-) -3,3- dimethoxy cyclobutane formonitrile HCNs (6.7g, 25.1mmol) and KOH N-BuOH (30ml) solution of (50% aqueous solution, 15g) heats 16h in 125 DEG C.Reactant mixture is concentrated under reduced pressure.Add Water (100mL), is extracted (2 × 100mL) with EtOAc.Aqueous phase is adjusted to pH~2 using 2N HCl/waters solution, extracted with EtOAc (3×100mL).Organic phase is dried over sodium sulfate, filters and is concentrated under reduced pressure, obtain for yellow solid target product (6.2g, 86% yield).Crude material need not be further purified and be used directly for next step.
LCMS(ESI)：M/z=309.0 [M+Na]+。
Step 6：1- (the fluoro- 4- aminomethyl phenyls of 2,5- bis-) -3,3- dimethoxy cyclobutane -1- methyl formates
To the methanol of 1- (the fluoro- 4- aminomethyl phenyls of 2,5- bis-) -3,3- dimethoxys cyclobutane formate (6g, 21mmol) SOCl is added in (25mL) solution2(3.74g, 31.5mmol), reactant mixture is stirred into 12h at room temperature.It is removed under reduced pressure molten Agent, residue are used as eluant, eluent using petroleum ether/EtOAc (8/1), obtained as light yellow oil by silica gel chromatography Target compound (5.5g, 87% yield).1H NMR(400MHz,DMSO-d6) δ 7.22 (dd, J=10Hz, J=6.4Hz, 1H), 7.13 (dd, J=11.2Hz, J=6.4Hz, 1H), 3.58 (s, 3H), 3.07 (s, 3H), 3.02 (s, 3H), 2.93 (d, J =13.2Hz, 2H), 2.59 (d, J=12.8Hz, 2H), 2.21 (d, J=1.6Hz, 3H).LCMS(ESI)：M/z=323.0 [M+ Na]+。
Step 7：1- (4- bromomethyl -2,5- difluorophenyls) -3,3- dimethoxys-cyclobutane formate methyl esters
By 1- (the fluoro- 4- methylphenyls of 2,5- bis-) -3,3- dimethoxys-cyclobutane formate methyl esters (3.0g, 10.0mmol) CHCl3(100mL) solution using NBS (2.13g, 12.0mmol) handle, then using benzoyl peroxide (165mg, 0.68mmol) handle, solution is flowed back 2h.Reactant is concentrated in vacuo, passes through silica gel chromatography (hexamethylene-EtOAc/ Hexamethylene 1:3) target compound (3.0g) of yellow oil, is obtained.LCMS(ESI)：M/z=479.2 [M+H]+.
Step 8：1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazine Alkane -2- ylmethyls)-phenyl] -3,3- dimethoxys-cyclobutane formate methyl esters
It will be obtained from product (3.0g, 7.9mmol), (3S, the 6R) -3- methyl -6- phenyl-thiazan 1,1- dioxies of step 7 The mixture of compound (1.2g, 5.3mmol), cesium carbonate (2.3g, 7.5mmol) and dry DMF (20mL) stirs at room temperature 16h.Reactant is diluted into (150mL) with EtOAc, uses H2O (150mL) is washed, and is then washed with salt solution (100mL), through sulfuric acid Magnesium is dried, evaporation, using purification by flash chromatography (EtOAc/ hexamethylenes 1:4–1:2) the target chemical combination for yellow oil, is obtained Thing (2.9g).
Step 9：1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazine Alkane -2- ylmethyls)-phenyl] -3- oxos-cyclobutane formate methyl esters
It will be obtained from mixture of the product (2.9g) of step 8 in acetone (100mL) and use conc.H2SO4(5 drop) processing. Solution is flowed back 45min, by H2O is added in the hot solution until initially forming precipitation.When evaporation section solvent, obtain white Color solid, is collected by filtration, and obtains the target compound (1.7g) for pale solid.1H NMR(300MHz,CDCl3)δ 7.50-7.36 (6H, m), 6.94 (1H, dd, J=6.2,10.1Hz), 4.49 (2H, dd, J=15.3,41.5Hz), 4.28- 4.25 (1H, m), 4.00 (1H, dd, J=3.4,12.9Hz), 3.91-3.81 (2H, m), 3.74-3.73 (3H, m), 3.51 (2H, Dd, J=2.6,17.0Hz), 2.74-2.58 (1H, m), 2.29-2.16 (1H, m), 1.84-1.73 (2H, m), 1.17 (3H, d, J =7.0Hz).LCMS(ESI),m/z,500[M+Na]+。
Step 10：1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiophene Piperazine alkane -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutane formate methyl esters
It will be obtained from the PhCH of the product (763mg, 1.6mmol) of step 93(20mL) solution uses methyl-magnesium-bromide in 0 DEG C (1.0mL, 3M Et2O solution) processing, persistently stir 0.75h.Reactant is quenched with MeOH (1mL), then with 0.1N HCl The aqueous solution (70mL) is quenched, and is diluted (2 × 70mL) with EtOAc, dries organic phase (MgSO4), filter, be concentrated in vacuo, using fast Fast chromatogram purification (1:2-1:1EtOAc- hexamethylenes), obtain the target compound (550mg) for foam.
Step 11：Anti-form-1-[bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, the λ * 6*- of 1- dioxo-6- phenyl-1 [1, 2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutane formate methyl esters
Will be obtained from THF (10mL) solution of the product (0.75g, 1.5mmol) of step 10 using lithium hydroxide (72mg, Water (10mL) solution processing 3.0mmol), persistently stirs 1h.By reactant H2O (50mL) dilutes, and is extracted with EtOAc (50mL) Take, dry (MgSO4) and be evaporated in vacuo, obtain the target compound (330mg) for colorless oil.1H NMR(400MHz, DMSO-d6)δ7.49-7.35(6H,m),7.23-7.15(2H,m),5.08(1H,s),4.60-4.48(2H,m),4.40-4.33 (1H,m),4.18-4.07(1H,m),3.58(3H,s),2.90-2.82(2H,m),2.47-2.38(1H,m),2.14-2.06 (1H, m), 1.85-1.63 (2H, m), 1.40 (3H, s), 1.13 (3H, d, J=7.4Hz).
Step 12：Anti-form-1-[bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, the λ * 6*- of 1- dioxo-6- phenyl-1 [1, 2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutane formate
The 1N NaOH aqueous solution is added into MeOH (18mL) solution of the product (330mg, 0.69mmol) obtained from step 11 (3.5mL,3.5mmol).Reactant is kept into 18h at room temperature, 7h is heated in 35 DEG C, then keeps 56h at room temperature.Will be anti- Answer thing 1N HCl/waters solution (50mL) to dilute, extracted with EtOAc (70mL), then use CH2Cl2(50mL) is extracted.By having for merging Partially dried (the MgSO of machine4) and evaporate, obtain target compound.
Step 13：Trans -5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazine Alkane -2- bases] methyl] phenyl] -3- hydroxy-3-methyls-cyclobutyl] -3H-1,3,4- oxadiazole -2- ketone
In 0 DEG C Et is added into THF (7mL) solution of the product (260mg, 0.54mmol) obtained from step 123N(104μ L,0.73mmol).Add carbonochloridic acid isobutyl (104 μ l, 0.66mmol), add after 0.5h hydrazine hydrate (153 μ l, 1.6mmol), reactant is warmed to room temperature.Reactant dilutes (70mL) with EtOAc, is washed with the sodium bicarbonate aqueous solution of saturation Wash (40mL), dry (MgSO4) and be evaporated in vacuo.Dry DMF (1.5mL) is dissolved the residue in, is cooled to 0 DEG C, adds Et3N (91 μ L, 0.66mmol), then adds 1,1- carbonyl dimidazoles (89mg, 0.55mmol).Reactant is dilute with EtOAc (70mL) Release, use H2O (2 × 50mL) is washed, and dries (MgSO4) and evaporate.Pass through purification by flash chromatography (EtOAc/ hexamethylenes 1:2–1:1), Then crystallized in EtOAc/ hexamethylenes, obtain the target compound (46mg) for white solid.1H NMR(400MHz,DMSO- d6)δ7.48-7.44(2H,m),7.43-7.35(3H,m),7.29-7.18(2H,m),5.19-5.18(1H,m),4.61-4.49 (2H, m), 4.41-4.34 (1H, m), 4.16-4.10 (1H, m), 2.94 (2H, d, J=13.2Hz), 2.66 (2H, d, J= 13.2Hz), 2.47-2.37 (1H, m), 2.14-2.06 (1H, m), 1.86-1.73 (1H, m), 1.67 (1H, dd, J=2.4, 14.2Hz), 1.27 (3H, s), 1.13 (3H, d, J=7.3Hz).LCMS(ESI)：M/z=520.1 [M+H]+。
Embodiment 3：Cis -5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazine Alkane -2- bases] methyl] phenyl] -3- hydroxy-3-methyls-cyclobutyl] -3H-1,3,4- oxadiazole -2- ketone
Step 1：Cis -1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ * 6*- of 1- dioxo -6- phenyl -1 [1, 2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutane formate
The aqueous phase acidifying of the step 11 of embodiment 2 is will be obtained from, with EtOAc and CH2Cl2Extraction, the extract of merging is dried (MgSO4) and evaporate, obtain the target compound (390mg) for solid.
Step 2：Cis -5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazine Alkane -2- bases] methyl] phenyl] -3- hydroxy-3-methyls-cyclobutyl] -3H-1,3,4- oxadiazole -2- ketone
So that the product obtained from step 1 reacts as described in the step 13 of embodiment 2, target compound is obtained.1H NMR (400MHz,DMSO-d6)δ12.23-12.11(1H,m),7.48-7.35(6H,m),7.27-7.20(1H,m),5.22-5.20 (1H, m), 4.61-4.50 (2H, m), 4.38 (1H, d, J=17.6Hz), 4.16-4.02 (1H, m), 2.90-2.82 (2H, m), 2.70 (2H, dd, J=4.2,12.0Hz), 2.48-2.38 (1H, m), 2.14-2.06 (1H, m), 1.85-1.63 (2H, m), 1.15-1.08(6H,m)；LCMS(ESI)：M/z=520.1 [M+H]+。
Embodiment 4：5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base] methyl] phenyl] -3,3- dimethoxys-cyclobutyl] -3H-1,3,4- oxadiazole -2- ketone
Step 1：1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazine Alkane -2- ylmethyls)-phenyl] -3,3- dimethoxys-cyclobutane formate
To 1- [bis- fluoro- 4- of 2,5- (and (3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ * 6*- [1,2] thiazan - 2- ylmethyls)-phenyl] -3,3- dimethoxys-cyclobutane formate methyl esters (2.18g, 4.17mmol) THF (20mL) and H2O LiOH (0.2g, 8.34mmol) is added in the solution of (20mL).Reactant is concentrated in vacuo after 16h, is used directly for next Step.LCMS(ESI)：M/z=532 [M+Na]+。
Step 2：5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base] methyl] phenyl] -3,3- dimethoxys-cyclobutyl] -3H-1,3,4- oxadiazole -2- ketone
The product that will be obtained from step 1 reacts as described in the step 13 of embodiment 2, obtains target compound.1H NMR (400MHz,DMSO-d6) δ 7.45-7.29 (6H, m), 7.21 (1H, dd, J=6.2,11.1Hz), 4.57-4.46 (2H, m), 4.35 (1H, d, J=17.8Hz), 4.13-3.93 (1H, m), 3.05-2.99 (9H, m), 2.74 (2H, dd, J=4.5, 12.0Hz), 2.44-2.35 (1H, m), 2.11-2.03 (1H, m), 1.83-1.70 (1H, m), 1.64 (1H, dd, J=2.3, 14.2Hz),1.12-1.08(3H,m)；LCMS(ESI),m/z,542[M+H]+.
Embodiment 5：5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base] methyl] phenyl] -3- oxo-cyclobutyls] -3H-1,3,4- oxadiazole -2- ketone
Step 1：5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base] methyl] phenyl] -3- oxo-cyclobutyls] -3H-1,3,4- oxadiazole -2- ketone
To 5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] -3,3- dimethoxys-cyclobutyl] and -3H-1,3,4- oxadiazole -2- ketone (0.27g, 0.5mmol) acetone (15mL) Conc.H is added in solution2SO4(2 drop), by reactant return stirring 2h.Reactant is by adding EtOAc (30mL) quenchings.Very Sky removes acetone, reactant NaHCO3The aqueous solution washs, and dries (Na2SO4) and be concentrated under reduced pressure, obtain target compound.1H NMR(400MHz,DMSO-d6) δ 7.49-7.27 (7H, m), 4.62-4.53 (2H, m), 4.41 (1H, d, J=17.9Hz), 4.18-4.10(1H,m),3.95-3.81(3H,m),2.48-2.40(1H,m),2.14-2.08(1H,m),1.91-1.76(1H, M), 1.68 (1H, dd, J=2.3,14.2Hz), 1.40 (1H, s), 1.18-1.07 (3H, m).LCMS(ESI)：M/z=504 [M+ H]+。
Embodiment 6：Trans -5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazine Alkane -2- bases] methyl] phenyl] -3- hydroxy-cyclobutyls] -3H-1,3,4- oxadiazole -2- ketone
Step 1：Trans -5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazine Alkane -2- bases] methyl] phenyl] -3- hydroxy-cyclobutyls] -3H-1,3,4- oxadiazole -2- ketone
To 5- [1- [bis- fluoro- 4- of 2,5- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl] -3- oxo-cyclobutyls] and -3H-1,3,4- oxadiazole -2- ketone (245mg, 0.5mmol) MeOH (2.5mL) and THF NaBH is added in (2.5mL) solution4(38mg,1mmol).After 2h, by reactant EtOAc (10mL) and H2O (10mL) dilutes, Organic phase salt water washing, dry (MgSO4) and evaporate.Purified by SFC, obtain the target compound for white solid (68mg)。1H NMR(400MHz,DMSO-d6) δ 7.46-7.34 (5H, m), 7.22-7.14 (2H, m), 5.30 (1H, d, J= 6.9Hz),4.57-4.47(2H,m),4.38-4.23(2H,m),4.14-4.04(1H,m),3.12-3.03(2H,m),2.45- 2.32 (3H, m), 2.11-2.05 (1H, m), 1.84-1.71 (1H, m), 1.64 (1H, dd, J=2.3,14.2Hz), 1.12- 1.08(3H,m)；LCMS(ESI),m/z,506[M+H]+。
Embodiment 7：4- [the fluoro- 4- of 3- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first Base] phenyl]-N- (oxetanes -3- bases) oxinane -4- formamides
Step 1：4- (the fluoro- 4- of 3- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) tetrahydrochysene -2H- pyrans -4- methyl formates
(3S, 6R) -2- [(the bromo- 2- fluoro-phenyls of 4-) methyl] -3- methyl -6- phenyl-thiazan 1,1- is added into flask Dioxide (10g, 24mmol), two (dibenzylidene benzylacetone) palladiums (1.39g, 2.4mmol) and 2- dicyclohexyl phosphino- -2', 6'- bis--isopropoxies -1,1'- biphenyl (1.15g, 2.4mmol), is filled with nitrogen 2min.Then add THF (120mL), tetrahydrochysene Pyrans -4- methyl formates (8.1mL, 61mmol) and zinc chloride 2,2,6,6- tetramethyl piperidine lithium chlorides compound (93mL, 0.65M THF solution), reactant is stirred into 2h in 60 DEG C.Reactant is cooled to room temperature, with the NH4Cl aqueous solution of saturation (100mL) is quenched, and is extracted (3 × 100mL) with EtOAc.The organic extract of merging is dried over magnesium sulfate, filters, and concentration, passes through Silica gel chromatography (0%-100% EtOAc n-heptane solutions), obtain target compound (6.5g, 56% yield).1H NMR(400MHz,DMSO-d6)δ7.55–7.48(m,1H),7.48–7.43(m,2H),7.43–7.33(m,3H),7.26–7.20 (m,1H),7.18–7.12(m,1H),4.58–4.47(m,2H),4.41–4.32(m,1H),4.20–4.06(m,1H),3.85– 3.75(m,2H),3.66–3.60(s,3H),3.47–3.36(m,2H),2.47–2.31(m,3H),2.15–2.05(m,1H), 1.96-1.74 (m, 3H), 1.71-1.61 (m, 1H), 1.15-1.07 (d, J=6.9Hz, 3H).
Step 2：4- (the fluoro- 4- of 3- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) tetrahydrochysene -2H- pyrans -4- formic acid
To 4- [the fluoro- 4- of 3- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] methyl] phenyl] Lithium hydroxide hydration is added in the THF (60mL) and water (20mL) solution of oxinane -4- methyl formates (5.67g, 12mmol) Thing (5.0g, 119mmol), 72h is stirred by reactant at room temperature.(50mL) is diluted with water in reactant, molten using 1N HCl/waters Liquid adjusts pH to 1.Product is extracted (3 × 75mL) with EtOAc, dried over magnesium sulfate, is filtered, and concentration is pure by silica gel chromatograph Change (0%-100% EtOAc n-heptane solutions), obtain target compound (4.0g, 73% yield).1H NMR(400MHz, DMSO-d6)δ7.54–7.43(m,3H),7.43–7.33(m,3H),7.28–7.23(m,1H),7.18–7.12(m,1H), 4.58–4.46(m,2H),4.42–4.32(m,1H),4.19–4.05(m,1H),3.84–3.74(m,2H),3.51–3.38(m, 2H),2.47–2.41(m,1H),2.38–2.30(m,2H),2.16–2.06(m,1H),1.88–1.74(m,3H),1.72–1.61 (m, 1H), 1.15-1.05 (d, J=6.8Hz, 3H).
Step 3：4- (the fluoro- 4- of 3- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl)-N- (oxetanes -3- bases) tetrahydrochysene -2H- pyrans -4- formamides
4- [the fluoro- 4- of 3- [[(3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases] first is added into bottle Base] phenyl] oxinane -4- formic acid (50mg, 0.11mmol), oxetanes -3- amine (24mg, 0.33mmol), N, N- bis- NMF (14mL) and triethylamine (0.045mL, 0.33mmol).Into reactant mixture add HATU (63mg, 0.16mmol), reactant is stirred into 16h at room temperature.Reactant is distributed between water and dichloromethane, organic layer uses phase Short column separation is separated, concentration, is purified by preparative HPLC, obtains target compound (17.9mg, 32% yield).1H NMR (400MHz,DMSO-d6) δ 8.28 (d, J=5.9Hz, 1H), 7.53-7.43 (m, 3H), 7.43-7.33 (m, 3H), 7.20 (dd, J=8.3,1.8Hz, 1H), 7.11 (dd, J=12.2,1.9Hz, 1H), 4.81-4.68 (m, 1H), 4.64 (t, J=6.8Hz, 2H),4.58–4.45(m,2H),4.43–4.31(m,3H),4.20–4.05(m,1H),3.84–3.68(m,2H),3.51–3.36 (m,2H),2.47–2.35(m,3H),2.16–2.07(m,1H),1.92–1.73(m,3H),1.72–1.60(m,1H),1.10 (d, J=6.8Hz, 3H).
Embodiment 8：Trans-[3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, λ of 1- dioxo -6- phenyl -16-[1, 2] thiazan -2- ylmethyls)-phenyl] -3- (5- oxo -4,5- dihydros-[and 1,3,4] oxadiazole -2- bases)-cyclobutyl]-acetonitrile With cis-[3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- bases Methyl)-phenyl] -3- (5- oxo -4,5- dihydros-[and 1,3,4] oxadiazole -2- bases)-cyclobutyl]-acetonitrile
Step 1：1- (the fluoro- 4- methylphenyls of 2,5- bis-) -3- oxos-cyclobutane formate methyl esters
So that 1- (the fluoro- 4- aminomethyl phenyls of 2,5- bis-) -3,3- dimethoxy cyclobutane formates methyl esters (4.50g, 15.0mmol) reacted according to step 9 methods described of embodiment 2, obtain the target compound (3.80g) for solid.1H NMR (300MHz,CDCl3)δ6.96-6.89(2H,m),3.89-3.82(2H,m),3.74(3H,s),3.55-3.47(2H,m), 2.28 (3H, d, J=1.8Hz).LCMS(ESI)：M/z=276.9 [M+Na]+。
Step 2：3- cyanomethylenes -1- (the fluoro- 4- methylphenyls of 2,5- bis-)-cyclobutane formate methyl esters
Tertiary fourth is added in 0 DEG C of anhydrous THF (15mL) solution to cyano group phosphonic acids diethyl ester (585mg, 3.31mmol) Potassium alcoholate (3.31mL, 3.31mmol, 1M THF solution).Reactant is stirred into 5min in 0 DEG C, then adds the production obtained from step 1 Anhydrous THF (15mL) solution of thing (700mg, 2.76mmol).Reactant is warmed to room temperature into 2h, uses NH4Cl(sat.,aq., 30mL) it is quenched, is extracted (2 × 40mL) with EtOAc.The organic moiety of merging is dried over sodium sulfate and is concentrated in vacuo.By quick Chromatogram purification (0-60% EtOAc/ hexamethylenes), obtains the target compound (730mg) for grease.1H NMR (300MHz,CDCl3) δ 6.94-6.84 (2H, m), 5.28 (1H, dd, J=2.3,2.3Hz), 3.81-3.64 (5H, m), 3.49- 3.12 (2H, m), 2.26 (3H, d, J=1.8Hz).
Step 3：(cis/trans) -3- cyano methyls -1- (the fluoro- 4- methylphenyls of 2,5- bis-)-cyclobutane formate methyl esters
By the EtOAc (10mL) containing the product (720mg, 2.60mmol) obtained from step 2 and MeOH (2.0mL) solution Flask argon-degassed, then add palladium carbon (551mg, 0.331mmol, 5%wt).Mixture is deaerated with hydrogen, In hydrogen environment, 2h is stirred at room temperature.Reactant is filtered by diatomite, is concentrated in vacuo.Pass through purification by flash chromatography (0-60% EtOAc/ hexamethylenes), the target compound (658mg) for grease is obtained, be the 2 of diastereoisomer:1 is mixed Compound.1H NMR(300MHz,CDCl3)δ7.02-6.77(2H,m),3.70-3.66(3H,m),3.08-2.92(1H,m), 2.76-2.57 (4.67H, m), 2.44 (0.67H, d, J=6.0Hz), 2.35-2.22 (3.66H, m).
Step 4：(cis/trans) -1- (4- bromomethyl -2,5- difluorophenyls) -3- cyano methyls-cyclobutane formate first Ester
So that the product (658mg, 2.36mmol) obtained from step 3 reacts according to step 7 methods described of embodiment 2, obtain Target compound, it is the 2 of diastereoisomer:1 mixture (870mg).1H NMR(300MHz,CDCl3)δ7.14-6.83(2H, m),4.47-4.43(2H,m),3.73-3.67(3H,m),3.10-2.98(1H,m),2.77-2.58(4.33H,m),2.46 (0.67H, d, J=5.8Hz), 2.36-2.24 (1H, m).
Step 5：(cis/trans) -3- cyano methyls -1- [2,5- bis- fluoro- 4- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxies The λ of generation -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl]-cyclobutane formate methyl esters
So that the product (870mg) obtained from step 4 reacts according to step 8 methods described of embodiment 2, obtain as grease Target compound (797mg), it is the 2 of diastereoisomer:1 mixture.1H NMR(300MHz,CDCl3)δ7.50-7.35(6H, M), 7.00 (0.67H, dd, J=6.2,10.4Hz), 6.83 (0.33H, dd, J=6.2,10.1Hz), 4.58-4.35 (2H, m), 4.32-4.22(1H,m),4.04-3.96(1H,m),3.68(1H,s),3.6(2H,s),3.07-2.92(1H,m),2.74- 2.57 (5.66H, m), 2.45 (0.67H, d, J=6.0Hz), 2.34-2.18 (1.67H, m), 1.82-1.73 (2H, m), 1.18 (3H, d, J=6.6Hz).
Step 6：(cis/trans) -3- cyano methyls -1- [2,5- bis- fluoro- 4- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxies The λ of generation -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl]-cyclobutane formate
So that the product (797mg, 1.59mmol) obtained from step 5 is anti-according to step 12 methods described of embodiment 2 in 50 DEG C Should, the target compound (736mg) for grease is obtained, is the 2 of diastereoisomer:1 mixture.LCMS(ESI)：M/z= 489.2[M+H]+.
Step 7：Trans-[3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, λ of 1- dioxo -6- phenyl -16-[1,2] Thiazan -2- ylmethyls)-phenyl] -3- (5- oxo -4,5- dihydros-[1,3,4] oxadiazole -2- bases)-cyclobutyl]-acetonitrile and Cis-[3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- Ji Jia Base)-phenyl] -3- (5- oxo -4,5- dihydros-[and 1,3,4] oxadiazole -2- bases)-cyclobutyl]-acetonitrile
So that the product (736mg, 1.51mmol) obtained from step 6 reacts according to step 13 methods described of embodiment 2, obtain Target compound, it is the 2 of diastereoisomer:1 mixture.The diastereoisomer is purified by chiral SFC.Trans-[3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-benzene Base] -3- (5- oxo -4,5- dihydros-[and 1,3,4] oxadiazole -2- bases)-cyclobutyl]-acetonitrile.1H NMR(400MHz,DMSO-d6) δ 12.26 (1H, s), 7.48-7.36 (5H, m), 7.25-7.18 (2H, m), 4.61-4.49 (2H, m), 4.37 (1H, d, J= 17.9Hz), 4.17-4.09 (1H, m), 2.94 (2H, dd, J=8.5,10.4Hz), 2.85-2.74 (1H, m), 2.69 (2H, d, J =6.7Hz), 2.47-2.36 (3H, m), 2.14-2.07 (1H, m), 1.86-1.63 (2H, m), 1.13 (3H, d, J=6.9Hz). LCMS(ESI)：M/z=529.2 [M+H]+.Cis-[3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- The λ of phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- (5- oxo -4,5- dihydros-[1,3,4] oxadiazole -2- bases) - Cyclobutyl]-acetonitrile.1H NMR(400MHz,DMSO-d6)δ12.23-12.23(1H,s),7.51-7.36(6H,m),7.25(1H, Dd, J=6.2,11.3Hz), 4.61-4.51 (2H, m), 4.40 (1H, d, J=17.8Hz), 4.16-4.08 (1H, m), 2.85- 2.81 (2H, m), 2.73 (2H, d, J=6.2Hz), 2.68-2.54 (3H, m), 2.48-2.38 (1H, m), 2.14-2.07 (1H, M), 1.87-1.75 (1H, m), 1.71-1.64 (1H, m), 1.14 (3H, d, J=6.9Hz).LCMS(ESI)：M/z=529.2 [M +H]+。
Embodiment 9：Trans -5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl } -2- methyl -2,4- dihydros-[1,2,4] three Azoles -3- ketone and cis -5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiophene Piperazine alkane -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl } -2- methyl -2,4- dihydros-[1,2,4] triazole -3- ketone
Step 1：1- (the fluoro- 4- methylphenyls of 2,5- bis-) -3- oxos-cyclobutane formonitrile HCN
So that 1- (the fluoro- 4- aminomethyl phenyls of 2,5- bis-) -3,3- dimethoxy cyclobutane formonitrile HCN (3.30g, 12.4mmol) root Reacted according to step 9 methods described of embodiment 2, obtain the target compound (2.30g) for grease.1H NMR(300MHz, CDCl3) δ 7.15 (1H, dd, J=6.7,9.5Hz), 7.03 (1H, dd, J=5.8,10.9Hz), 4.05-3.97 (2H, m), 3.83-3.75 (2H, m), 2.30 (3H, d, J=1.8Hz).
Step 2：(cis/trans) -1- (the fluoro- 4- methylphenyls of 2,5- bis-) -3- hydroxy-3-methyls-cyclobutane formonitrile HCN
The solution of toluene (80mL) and THF (20mL) in -78 DEG C to the product (2.30g, 10.4mmol) obtained from step 1 Middle addition methyl-magnesium-bromide (4.51mL, 13.5mmol, 3.0M THF solution).Reactant is stirred into 45min in -78 DEG C, used NaHCO3(sat., aq., 100mL) is quenched, and is warmed to room temperature, is extracted (150mL) with EtOAc.Organic moiety is dried over sodium sulfate And it is concentrated in vacuo.By purification by flash chromatography (0-50% EtOAc/ hexamethylenes), the target compound for grease is obtained (1.53g).LCMS(ESI)：M/z=238.1 [M+H]+。
Step 3：(cis/trans) -1- (4- bromomethyl -2,5- difluorophenyls) -3- hydroxy-3-methyls-cyclobutane formonitrile HCN
So that the product (1.53g, 6.45mmol) obtained from step 2 reacts according to step 7 methods described of embodiment 2, obtain Target compound, it is the 1 of diastereoisomer:1 mixture (1.95g).1H NMR(300MHz,CDCl3)δ7.25-7.14(1H, m),7.05-6.96(1H,m),4.46-4.44(2H,m),3.07-2.98(2H,m),2.80-2.74(2H,m),2.27(1H,t, ), J=2.3Hz 1.75 (1.5H, s), 1.35 (1.5H, s).
Step 4：(cis/trans) -1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ6- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutane formonitrile HCN
So that the product (1.95g) obtained from step 3 reacts according to step 8 methods described of embodiment 2, target chemical combination is obtained Thing, it is the 1 of diastereoisomer:1 mixture (1.50g).1H NMR(300MHz,CDCl3)δ7.49-7.36(6H,m),6.99- 6.89 (1H, m), 4.53 (1H, d, J=17.3Hz), 4.40 (1H, d, J=17.1Hz), 4.32-4.23 (1H, m), 4.04- 3.97(1H,m),3.06-2.95(2H,m),2.82-2.63(3H,m),2.29-2.19(1H,m),1.97(0.5H,s),1.88 (0.5H,s),1.82-1.78(2H,m),1.74(1.5H,s),1.33(1.5H,s),1.19-1.14(3H,m)。
Step 5：(cis/trans)-acetic acid 3- cyano group -3- [2,5- bis- fluoro- 4- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxies The λ of generation -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -1- methyl-cyclobutyl esters
Into DCM (5mL) solution of the product (200mg, 0.435mmol) obtained from step 4 add acetic anhydride (0.164mL, 1.74mmol)、Et3N (0.303mL, 2.18mmol) and DMAP (8.0mg, 0.065mmol).Reactant is stirred at room temperature 1h, solvent is then removed in vacuum.By purification by flash chromatography (0-50% EtOAc/ hexamethylenes), the mesh for grease is obtained Mark compound (180mg).LCMS(ESI)：M/z=503.0 [M+H]+。
Step 6：(cis/trans)-acetic acid 3- carbamoyls -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- The λ of dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -1- methyl-cyclobutyl esters
To the IMS (2mL) and H of the product (180mg, 0.359mmol) obtained from step 52Hydrogen is added in O (0.5mL) solution Change (hydrido) (dimethyl phosphonous acid-kP) [hydrogen two (dimethyl phosphine acidic group (phosphinito)-kP)] platinum (II) (1.5mg, 3.6μmol).Reactant is heated to 85 DEG C of 2h, is subsequently cooled to room temperature 16h.Reactant is concentrated in vacuo, crude material is molten In EtOAc (40mL).Organic moiety salt water washing, it is dried over sodium sulfate and be concentrated in vacuo, obtain the targeted for grease Compound (186mg).LCMS(ESI)：M/z=521.0 [M+H]+。
Step 7：(cis/trans)-acetic acid 3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- benzene The λ of base -16- [1,2] thiazan -2- ylmethyls)-phenyl] -1- methyl -3- (1- methyl -5- oxo -4,5- dihydros -1H- [1,2, 4] triazole -3- bases)-cyclobutyl ester
To the de gassed solution of the anhydrous 1,2- dichloroethanes (4.0mL) of the product (186mg, 0.358mmol) obtained from step 6 Middle addition oxalyl chloride (41 μ L, 0.49mmol).Reactant is heated into 0.5h at room temperature, is then heated to 75 DEG C of 15min.Will be mixed Compound is cooled to room temperature, and solvent is removed in vacuum.Crude product is immediately dissolved in anhydrous DCM (4mL), adds 1-BOC-2- methyl hydrazines (65mg,0.44mmol).Reactant is stirred into 15min at room temperature, solvent is then removed in vacuum.Crude product is dissolved in DCM (4mL) With TFA (2mL), reactant is stirred into 1h at room temperature.Solvent is removed in vacuum, crude product is dissolved in EtOAc (30mL).Organic moiety Use NaHCO3(sat., aq., 30mL) is washed, dried over sodium sulfate and be concentrated in vacuo.Pass through purification by flash chromatography (0-100% EtOAc/ hexamethylenes, then 0-10% MeOH:DCM), the target compound (138mg) for grease is obtained.LCMS (ESI)：M/z=575.0 [M+H]+。
Step 8：Trans -5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1, 2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl } -2- methyl -2,4- dihydros-[1,2,4] triazole -3- Ketone and cis -5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan- 2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl } -2- methyl -2,4- dihydros-[1,2,4] triazole -3- ketone
K is added into MeOH (1.5mL) solution of the product (138mg, 0.240mmol) obtained from step 72CO3(63mg, 0.45mmol).Reactant is stirred into 3h, then adds NaOH (18mg, 0.45mmol) H2O (1.5mL solution).By reactant 35 DEG C of 1.5h are heated to, are subsequently cooled to room temperature, are neutralized with HCl (1M, aq., 10mL).Mixture is extracted with EtOAc (2 × 30mL), the organic moiety of merging is dried over sodium sulfate and is concentrated in vacuo.Diastereoisomer passes through MDAP purifies and separates.Trans- 5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls) - Phenyl] -3- hydroxy-3-methyls-cyclobutyl } -2- methyl -2,4- dihydros-[1,2,4] triazole -3- ketone1H NMR(400MHz, DMSO-d6)δ11.53(1H,s),7.48-7.36(5H,m),7.21-7.12(2H,m),5.07(1H,s),4.59-4.46(2H, M), 4.35 (1H, d, J=17.8Hz), 4.15-4.08 (1H, m), 3.21 (3H, s), 2.92 (2H, d, J=12.5Hz), 2.61- 2.54(2H,m),2.47-2.31(1H,m),2.13-2.06(1H,m),1.85-1.62(2H,m),1.16(3H,s),1.12 (3H, d, J=6.8Hz).LCMS(ESI)：M/z=533.3 [M+H]+.Cis -5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- Methyl isophthalic acid, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl } - 2- methyl -2,4- dihydros-[1,2,4] triazole -3- ketone1H NMR(400MHz,DMSO-d6)δ7.49-7.35(5H,m),7.28 (1H, dd, J=6.7,10.6Hz), 7.17 (1H, dd, J=6.2,11.2Hz), 4.59-4.48 (2H, m), 4.37 (1H, d, J= 17.7Hz), 4.16-4.07 (1H, m), 3.16 (3H, s), 2.79 (2H, d, J=11.2Hz), 2.66 (2H, d, J=11.7Hz), 2.47-2.39 (1H, m), 2.14-2.06 (1H, m), 1.86-1.73 (1H, m), 1.67 (1H, dd, J=2.1,14.2Hz), 1.13 (3H, d, J=7.2Hz), 1.08 (3H, s), NH and OH are not observed.LCMS(ESI)：M/z=533.3 [M+H]+。
Embodiment 10：Trans -5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methoxies methyl-cyclobutyl } -3H- [1,3,4] oxadiazole -2- ketone
Step 1：1- (the fluoro- 4- methylphenyls of 2,5- bis-) -3- methylene-cyclobutane formate methyl esters
Potassium tert-butoxide is added into THF (40mL) solution of the phenyl-bromide Phosphonium (4.08g, 11.4mmol) of first base three (12.0mL, 12.0mmol, 1M THF solution).Reactant is heated to 40 DEG C of 45min.After being cooled to 0 DEG C, 1- (2,5- is added Two fluoro- 4- methylphenyls) -3- oxos-cyclobutane formate methyl esters (2.40g, 9.52mmol) THF (40mL) solution.Will reaction Thing warms to room temperature, and stirs 1h, then adds salt solution (90mL).Mixture is extracted (120mL) with EtOAc, organic moiety warp Sodium sulphate is dry and is concentrated in vacuo.By purification by flash chromatography (0-25% EtOAc/ hexamethylenes), the mesh for grease is obtained Mark compound (2.00g).LCMS(ESI)：M/z=253.2 [M+H]+。
Step 2：(cis/trans) -5- (the fluoro- 4- methylphenyls of 2,5- bis-) -1- oxa-s-spiral shell [2.3] hexane -5- formic acid Methyl esters
3- Chloroperbenzoic acids are added into DCM (60mL) solution of the product (1.20g, 4.76mmol) obtained from step 1 (1.17g,5.24mmol).Reactant is stirred into 6h at room temperature, is then diluted with DCM (80mL), uses Na2S2O5(sat., aq.,50mL)、NaHCO3(sat., aq., 50mL) is washed, dried over sodium sulfate and be concentrated in vacuo.Pass through purification by flash chromatography (0-25% EtOAc/ hexamethylenes), the target compound (1.10g, 65%) for grease is obtained, be diastereoisomer 2:1 mixture.LCMS(ESI)：M/z=291.0 [M+Na]+。
Step 3：5- (4- bromomethyl -2,5- difluorophenyls) -1- oxa-s-spiral shell [2.3] hexane -5- methyl formates
To the CHCl of the product (1.60g, 5.97mmol) obtained from step 23In (80mL) solution add NBS (1.17g, 6.57mmol) and benzoyl peroxide (159mg, 0.657mmol).Reactant is heated into 4h in 70 DEG C, is subsequently cooled to room temperature 16h.Reactant is again heated to 70 DEG C of 1h, room temperature is subsequently cooled to, solvent is removed in vacuum.Pass through purification by flash chromatography (0- 25% EtOAc/ hexamethylenes), obtain 1.90g crude residues.DMA (15mL) is dissolved the residue in, then add (3S, 6R) -3- methyl -6- phenyl-thiazan -1,1- dioxide (820mg, 3.65mmol) and cesium carbonate (1.95g, 5.97mmol).Reactant is stirred into 16h at room temperature, then adds EtOAc (400mL).Organic moiety H2O(2× 400mL) wash, it is dried over sodium sulfate and be concentrated in vacuo.By purification by flash chromatography (25-70% EtOAc/ hexamethylenes), obtain It must be the target compound (1.20g) of foam, be the 2 of diastereoisomer:1 mixture.LCMS(ESI)：M/z= 492.0[M+H]+。
Step 4：Anti-form-1-[bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, λ of 1- dioxo-6- phenyl-16-[1,2] Thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methoxies methyl-cyclobutane formate methyl esters
Into MeOH (20mL) solution of the product (300mg, 0.611mmol) obtained from step 3 add sodium hydride (98mg, 2.4mmol, 60% dispersion liquid).Reactant is stirred into 15min at room temperature, is then heated to 50 DEG C of 3h.Reactant is cooled to Room temperature, solvent is removed in vacuum.Pass through the purification by flash chromatography (MeOH of 50-100% EtOAc/ hexamethylenes, then 10%: EtOAc), the target compound (140mg) for grease is obtained, is single diastereoisomer.LCMS(ESI)：M/z= 524.2[M+H]+。
Step 5：Trans -5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1, 2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methoxies methyl-cyclobutyl } -3H- [1,3,4] oxadiazole -2- ketone
Hydrazine hydrate is added into DMA (0.5mL) solution of the product (140m, 0.268mmol) obtained from step 4 (0.5mL).Mixture is heated into 16h in 50 DEG C, room temperature is subsequently cooled to, is diluted with EtOAc (40mL).Organic moiety H2O Wash (2 × 40mL), it is dried over sodium sulfate and be concentrated in vacuo.Crude material is dissolved in DMF (1.5mL), then adds Et3N(50 μ L, 0.45mmol) and CDI (56mg, 0.32mmol).Reactant is stirred into 0.5h at room temperature, then adds EtOAc (40mL).Organic moiety H2O (40mL) is washed, dried over sodium sulfate and be concentrated in vacuo.Pass through purification by flash chromatography (50- 80% EtOAc/ hexamethylenes), then use Et2O/ hexamethylenes are ground, and obtain the target compound (38mg) for solid.1H NMR (400MHz,DMSO-d6) δ 12.21 (1H, s), 7.48-7.36 (5H, m), 7.31 (1H, dd, J=6.5,10.3Hz), 7.23 (1H, dd, J=6.2,11.0Hz), 5.29 (1H, s), 4.61-4.49 (2H, m), 4.38 (1H, d, J=17.9Hz), 4.18- 4.08 (1H, m), 3.30 (2H, s), 3.28 (3H, s), 3.04 (2H, d, J=13.7Hz), 2.57 (2H, d, J=14.0Hz), 2.47-2.39 (1H, m), 2.13-2.06 (1H, m), 1.85-1.74 (1H, m), 1.67 (1H, dd, J=2.2,14.3Hz), 1.14 (3H, d, J=6.5Hz).LCMS(ESI)：M/z=550.3 [M+H]+。
Embodiment 11：Trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1, 2] thiazan -2- ylmethyls)-phenyl] -1- methyl -3- [(3- methvl-oxetan -3- ylmethyls)-amino]-cyclobutanol
Step 1：3- amino -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1, 2] thiazan -2- ylmethyls)-phenyl] -1- methyl-cyclobutanol
To anti-form-1-[bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, λ of 1- dioxo-6- phenyl-16- [1,2] thiazine Alkane -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutane formate (1.50g, 3.13mmol) dioxane (50mL) it is molten Et is added in liquid3N (0.872mL, 6.26mmol) and diphenylphosphorylazide (0.809mL, 3.75mmol).Will reaction Thing heats 45min in 80 DEG C, is subsequently cooled to room temperature, adds HCl (aq., 1M, 30mL).Reactant is stirred at room temperature 45min, then use Et2O (30mL) is extracted.Water layer NaOH (aq., 1M) alkalizes, and is extracted (2 × 40mL) with EtOAc.Merge Organic moiety is dried over sodium sulfate and is concentrated in vacuo, and obtains the target compound for solid.1HNMR(400MHz,DMSO-d6)δ 7.48-7.35 (5H, m), 7.15 (1H, dd, J=6.2,11.2Hz), 7.02 (1H, dd, J=6.5,10.6Hz), 4.70 (1H, S), 4.57-4.46 (2H, m), 4.34 (1H, d, J=17.7Hz), 4.16-4.09 (1H, m), 2.47-2.38 (3H, m), 2.20 (2H, d, J=11.6Hz), 2.14-2.07 (1H, m), 2.00-1.95 (2H, m), 1.91-1.75 (1H, m), 1.70-1.63 (1H, m), 1.48 (3H, s), 1.11 (3H, d, J=6.9Hz).
Step 2：Trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1,2] Thiazan -2- ylmethyls)-phenyl] -1- methyl -3- [(3- methvl-oxetan -3- ylmethyls)-amino]-cyclobutanol
3- is added into 2,2,2 tfifluoroethyl alcohol (2.0mL) solution of the product (100mg, 0.222mmol) obtained from step 1 Methy oxetane -3- formaldehyde (40mg, 0.40mmol).Reactant is heated to 40 DEG C of 15min, then adds sodium borohydride (15mg,0.40mmol).Reactant is heated into 15min in 40 DEG C, solvent is removed in vacuum.Pass through purification by flash chromatography (100% EtOAc), Et is then used2O is ground, and obtains the target compound (37mg) for solid.1H NMR(400MHz,DMSO-d6)δ 7.49-7.36 (5H, m), 7.16 (1H, dd, J=6.1,11.1Hz), 7.03 (1H, dd, J=6.4,10.5Hz), 4.82 (1H, S), 4.59-4.46 (2H, m), 4.36 (1H, d, J=17.7Hz), 4.23 (2H, d, J=5.6Hz), 4.14-4.10 (3H, m), 2.47-2.39 (1H, m), 2.36-2.22 (6H, m), 2.14-2.06 (1H, m), 2.00 (1H, dd, J=8.1,8.1Hz), 1.86-1.74 (1H, m), 1.67 (1H, dd, J=2.2,14.2Hz), 1.45 (3H, s), 1.14 (3H, s), 1.12 (3H, d, J= 7.0Hz).LCMS(ESI)：M/z=535.1 [M+H]+。
Embodiment 12：Anti-form-1-{ 1- [bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, λ of 1- dioxo-6- phenyl-16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutylmethyl } -1H- pyrazine -2- ketone
Step 1：Anti-form-1-[bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, λ of 1- dioxo-6- phenyl-16-[1,2] Thiazan -2- ylmethyls)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxies methoxyl group)-cyclobutane formate methyl esters
To anti-form-1-[bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, λ of 1- dioxo-6- phenyl-16- [1,2] thiazine Alkane -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutane formate methyl esters (2.50g, 5.07mmol) DCM (50mL) it is molten In liquid add 2- (trimethyl silyl) ethyl-methyl chlorine (2.25mL, 12.7mmol) and diisopropylethylamine (1.76mL, 10.1mmol).Reactant is stirred into 16hr at room temperature.Mixture is diluted with DCM (50mL), organic moiety salt water washing (50mL), it is dried over sodium sulfate and be concentrated in vacuo.By purification by flash chromatography (0-50% EtOAc/ hexamethylenes), it is The target compound (1.40g) of grease.1H NMR(300MHz,CDCl3) δ 7.51-7.34 (6H, m), 6.94 (1H, dd, J= ), 6.6,10.4Hz 4.68 (2H, s), 4.52 (1H, d, J=17.3Hz), 4.40 (1H, d, J=17.2Hz), 4.33-4.23 (1H, m), 4.00 (1H, dd, J=3.5,12.9Hz), 3.68 (3H, s), 3.62-3.55 (2H, m), 3.03-2.93 (2H, m), 2.73 (2H, d, J=12.1Hz), 2.69-2.59 (1H, m), 2.30-2.19 (1H, m), 1.82-1.74 (2H, m), 1.48 (3H, S), 1.17 (3H, d, J=6.9Hz), 0.93-0.86 (2H, m), 0.00 (9H, s).LCMS(ESI)：M/z=646.3 [M+Na ]+。
Step 2：Trans-[1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, λ of 1- dioxo -6- phenyl -16-[1,2] Thiazan -2- ylmethyls)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxies methoxyl group)-cyclobutyl]-methanol
In 0 DEG C DIBAL-H is added into DCM (23mL) solution of the product (1.40g, 2.25mmol) obtained from step 1 (6.7mL, 6.7mmol, 1.0M DCM solution).Reactant is warmed to room temperature, stirs 1hr.By reactant potassium sodium tartrate (sat., aq., 20mL) is quenched, and is stirred 30 minutes.Layering, organic moiety is dried over sodium sulfate and is concentrated in vacuo.Pass through quick color Spectrum purifying (0-60% EtOAc/ hexamethylenes), obtains the target compound (1.20g) for grease.1H NMR(300MHz, CDCl3) δ 7.51-7.35 (6H, m), 6.85 (1H, dd, J=6.3,10.4Hz), 4.69 (2H, s), 4.53 (1H, d, J= 17.1Hz), 4.39 (1H, d, J=17.2Hz), 4.34-4.22 (1H, m), 4.01 (1H, dd, J=3.9,12.7Hz), 3.77 (2H, d, J=5.9Hz), 3.61-3.54 (2H, m), 2.71-2.58 (3H, m), 2.50-2.41 (2H, m), 2.25 (1H, ddd, J =3.5,7.0,14.1Hz), 1.84-1.74 (2H, m), 1.53 (3H, s), 1.37 (1H, t, J=6.1Hz), 1.19 (3H, d, J =6.9Hz), 0.92-0.86 (2H, m), 0.02-0.00 (9H, m).LCMS(ESI)：M/z=618.4 [M+Na]+。
Step 3：Trans-(3S, 6R) -2- bis- fluoro- 4- of 2,5- [1- iodomethyl -3- methyl -3- (2- trimethylsilyls - (ethoxymethyl) epoxide)-cyclobutyl]-benzyl } -3- methyl -6- phenyl-[1,2] thiazan 1,1- dioxide
Into toluene (30mL) solution of the product (1.20g, 2.02mmol) obtained from step 2 add triphenyl phasphine (1.06g, 4.03mmol), imidazoles (274mg, 4.03mmol) and iodine (872mg, 3.43mmol).Reactant is heated to 70 DEG C of 2hr, then Room temperature is cooled to, uses Na2S2O3(0.1M, aq., 30mL) is quenched, and is extracted (100mL) with EtOAc.Organic moiety is done through sodium sulphate It is dry and be concentrated in vacuo.By purification by flash chromatography (0-60% EtOAc/ hexamethylenes), the target compound for grease is obtained (1.32g)。1H NMR(400MHz,DMSO-d6) δ 7.51-7.39 (5H, m), 7.39-7.33 (1H, m), 6.83 (1H, dd, J= ), 6.5,10.4Hz 4.67 (2H, s), 4.54 (1H, d, J=16.9Hz), 4.42 (1H, d, J=16.9Hz), 4.33-4.24 (1H, m), 4.01 (1H, dd, J=3.6,12.9Hz), 3.68 (2H, s), 3.59-3.52 (2H, m), 2.77 (2H, d, J= 12.5Hz), 2.72-2.60 (1H, m), 2.45 (2H, d, J=14.2Hz), 2.30-2.21 (1H, m), 1.84-1.75 (2H, m), 1.55 (3H, s), 1.18 (3H, d, J=7.0Hz), 0.92-0.85 (2H, m), 0.00 (9H, s).
(ESI)：M/z=728.3 [M+Na]+。
Step 4：Anti-form-1-[1- [bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, λ of 1- dioxo-6- phenyl-16-[1, 2] thiazan -2- ylmethyls)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxies methoxyl group)-cyclobutylmethyl] - 1H- pyrazine -2- ketone
2- HYDROXYPYRAZINEs are added into DMA (1.0mL) solution of the product (200mg, 0.284mmol) obtained from step 3 (82mg, 0.85mmol) and cesium carbonate (277mg, 0.851mmol).Reactant is heated to 80 DEG C of 16h, is subsequently cooled to room Temperature, use H2O (10mL) dilutes, and is extracted (50mL) with EtOAc.Organic moiety is dried over sodium sulfate with salt water washing (3 × 30mL) And it is concentrated in vacuo.By purification by flash chromatography (20-100% EtOAc/ hexamethylenes), the target compound for grease is obtained (47mg)。1H NMR(300MHz,CDCl3) δ 8.12 (1H, d, J=1.0Hz), 7.53-7.39 (6H, m), 6.93 (1H, d, J= 4.4Hz), 6.63 (1H, dd, J=6.3,10.2Hz), 6.08 (1H, dd, J=1.0,4.4Hz), 4.67 (2H, s), 4.55 (1H, D, J=17.0Hz), 4.44-4.36 (2H, m), 4.35-4.24 (2H, m), 4.03 (1H, dd, J=3.5,12.8Hz), 3.59- 3.52(2H,m),2.81-2.61(5H,m),2.32-2.22(1H,m),1.85-1.76(2H,m),1.71(3H,s),1.17 (3H, d, J=6.9Hz), 0.92-0.84 (2H, m), 0.00 (9H, s).LCMS(ESI)：M/z=674.3 [M+H]+。
Step 5：Anti-form-1-{ 1- [bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, λ of 1- dioxo-6- phenyl-16-[1, 2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutylmethyl } -1H- pyrazine -2- ketone
HCl (4.0M dioxies six are added into MeOH (3.0mL) solution of the product (47mg, 70 μm of ol) obtained from step 4 Ring solution, 2.0mL).Reactant is stirred into 0.5h at room temperature, solvent is then removed in vacuum.Crude product is dissolved in EtOAc (30mL) And NaHCO3(sat., aq., 30mL), layering.Organic moiety is dried over sodium sulfate and is concentrated in vacuo.Purified, obtained by MDAP For the target compound of solid.1H NMR(400MHz,DMSO-d6) δ 7.87 (1H, d, J=1.1Hz), 7.49-7.37 (5H, m), 7.11 (1H, dd, J=6.2,11.2Hz), 6.97 (1H, d, J=4.4Hz), 6.82 (1H, dd, J=6.4,10.6Hz), 6.72 (1H, dd, J=1.0,4.4Hz), 4.91 (1H, s), 4.56-4.44 (2H, m), 4.34 (1H, d, J=17.4Hz), 4.25 (2H, S), 4.11 (1H, ddd, J=1.8,6.9,11.9Hz), 2.72-2.63 (2H, m), 2.48-2.38 (3H, m), 2.14-2.06 (1H, m), 1.87-1.77 (1H, m), 1.66 (1H, dd, J=2.2,14.3Hz), 1.42 (3H, s), 1.08 (3H, d, J= 6.8Hz).LCMS(ESI)：M/z=544.3 [M+H]+。
Embodiment 13：Trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1, 2] thiazan -2- ylmethyls)-phenyl] -1- methyl -3- (pyrazine -2- base epoxides methyl)-cyclobutanol
Step 1：Trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1,2] Thiazan -2- ylmethyls)-phenyl] -1- methyl -3- (pyrazine -2- base epoxides methyl)-cyclobutanol
(3S, 6R) -2- { bis- fluoro- 4- of 2,5- [3- methyl isophthalic acids-(pyrazine -2- base oxygen are separated also according to the step 4 of embodiment 12 Ylmethyl) -3- (2- trimethylsilyl-ethoxies (thoxy) methoxyl group)-cyclobutyl]-benzyl } -3- methyl -6- phenyl - [1,2] thiazan 1,1- dioxide (87mg, 0.13mmol), react and purify according to step 5 methods described of embodiment 12, obtain Obtain solid target compound.1H NMR(400MHz,DMSO-d6) δ 8.17 (1H, d, J=1.4Hz), 8.13 (1H, d, J= 2.6Hz), 8.08 (1H, dd, J=1.4,2.8Hz), 7.48-7.36 (5H, m), 7.14 (1H, dd, J=6.2,11.2Hz), 7.07 (1H, dd, J=6.7,10.5Hz), 4.98 (1H, s), 4.57-4.44 (4H, m), 4.33 (1H, d, J=17.8Hz), 4.15-4.07(1H,m),2.57-2.52(2H,m),2.49-2.38(3H,m),2.13-2.06(1H,m),1.85-1.72(1H, M), 1.69-1.62 (1H, m), 1.37 (3H, s), 1.08 (3H, d, J=6.8Hz).LCMS(ESI)：M/z=544.3 [M+H]+。
Embodiment 14：5- { (R) -1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- methyl-ring but-2-ene base } -3H- [1,3,4] oxadiazole -2- ketone and 5- { (S) -1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- Ji Jia Base)-phenyl] -3- methyl-ring but-2-ene base } -3H- [1,3,4] oxadiazole -2- ketone
Step 1：(R/S) -1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1,2] Thiazan -2- ylmethyls)-phenyl] -3- methyl-ring but-2-ene acid methyl esters
To cis -1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazine Alkane -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutane formate methyl esters (2.00g, 4.06mmol) DCM (50mL) it is molten Thionyl chloride (5.0mL) is added in liquid.Reactant is stirred into 4hr at room temperature, solvent is then removed in vacuum.Pass through flash chromatography Purify (25-70% EtOAc/ hexamethylenes), obtain the target compound (1.30g) for grease, be the mixed of olefin isomer Compound.LCMS(ESI)：M/z=476.3 [M+H]+。
Step 2：(R/S) -1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1,2] Thiazan -2- ylmethyls)-phenyl] -3- methyl-ring but-2-ene acid
So that the product (650mg, 1.37mmol) obtained from step 1 is anti-in 50 DEG C according to step 12 methods described of embodiment 2 Should, target compound is obtained, is the mixture (580mg) of olefin isomer.LCMS(ESI)：M/z=462.3 [M+H]+。
Step 3：5- { (R) -1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1, 2] thiazan -2- ylmethyls)-phenyl] -3- methyl-ring but-2-ene base } -3H- [1,3,4] oxadiazole -2- ketone and 5- { (S) -1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-benzene Base] -3- methyl-ring but-2-ene base } -3H- [1,3,4] oxadiazole -2- ketone
So that the product (580mg, 1.26mmol) obtained from step 2 reacts according to step 13 methods described of embodiment 2, obtain Target compound, it is the mixture of olefin isomer.The isomers passes through chiral SFC purifies and separates.5- { (R) -1- [2,5- bis- Fluoro- 4- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- first Base-ring but-2-ene base } -3H- [1,3,4] oxadiazole -2- ketone1H NMR(400MHz,DMSO-d6)δ12.15(1H,br.s), 7.49-7.35 (5H, m), 7.31 (1H, dd, J=6.3,10.2Hz), 7.25 (1H, dd, J=5.9,10.6Hz), 6.32 (1H, S), 4.60-4.50 (2H, m), 4.38 (1H, d, J=17.8Hz), 4.16-4.08 (1H, m), 3.25 (1H, d, J=14.7Hz), 2.83 (1H, d, J=13.6Hz), 2.48-2.39 (1H, m), 2.13-2.07 (1H, m), 1.86-1.74 (4H, m), 1.67 (1H, Dd, J=2.2,14.3Hz), 1.13 (3H, d, J=6.9Hz).LCMS(ESI)：M/z=524.2 [M+Na]+。5-{(S)-1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-benzene Base] -3- methyl-ring but-2-ene base } -3H- [1,3,4] oxadiazole -2- ketone1H NMR(400MHz,DMSO-d6)δ12.15(1H, ), br.s 7.49-7.34 (5H, m), 7.31 (1H, dd, J=6.3,10.2Hz), 7.25 (1H, dd, J=6.0,10.5Hz), 6.33 (1H, s), 4.61-4.50 (2H, m), 4.38 (1H, d, J=17.8Hz), 4.15-4.08 (1H, m), 3.26 (1H, d, J= 14.8Hz), 2.83 (1H, d, J=13.5Hz), 2.47-2.39 (1H, m), 2.14-2.07 (1H, m), 1.86-1.74 (4H, m), 1.71-1.64 (1H, m), 1.12 (3H, d, J=6.8Hz).LCMS(ESI)：M/z=524.2 [M+Na]+。
Embodiment 15：Trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1, 2] thiazan -2- ylmethyls)-phenyl] -3- [(S) -1- hydroxyls -2- (1H- [1,2,4] triazole -3- bases)-ethyl] -1- methyl - Cyclobutanol and trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan- 2- ylmethyls)-phenyl] -3- [(R) -1- hydroxyls -2- (1H- [1,2,4] triazole -3- bases)-ethyl] -1- methyl-cyclobutanol
Step 1：Anti-form-1-[bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, λ of 1- dioxo-6- phenyl-16-[1,2] Thiazan -2- ylmethyls)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxies methoxyl group)-cyclobutane formaldehyde
To trans-[1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, λ of 1- dioxo -6- phenyl -16- [1,2] thiazine Alkane -2- ylmethyls)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxies methoxyl group)-cyclobutyl]-methanol (700mg, Added in DCM (20mL) solution 1.18mmol) and wear this Martin's oxidant (698mg, 1.65mmol).By reactant at room temperature 1.5h is stirred, is then diluted with DCM (50mL).Organic moiety Na2S2O5(sat.,aq.,40mL)、NaHCO3(sat.,aq., 40mL) wash, it is dried over sodium sulfate and be concentrated in vacuo.By purification by flash chromatography (0-70% EtOAc/ hexamethylenes), obtain For the target compound (660mg) of grease.1H NMR(300MHz,CDCl3) δ 9.62 (1H, d, J=1.8Hz), 7.50-7.38 (6H, m), 6.84 (1H, dd, J=6.0,10.1Hz), 4.70 (2H, s), 4.53 (1H, d, J=17.2Hz), 4.40 (1H, d, J =17.1Hz), 4.34-4.22 (1H, m), 4.01 (1H, dd, J=3.5,12.8Hz), 3.63-3.56 (2H, m), 2.90 (2H, Dd, J=1.0,13.7Hz), 2.65 (3H, d, J=13.6Hz), 2.24 (1H, ddd, J=3.5,7.1,14.2Hz), 1.83- 1.74 (2H, m), 1.40 (3H, s), 1.16 (3H, d, J=6.9Hz), 0.93-0.86 (2H, m), 0.00 (9H, s).LCMS (ESI)：M/z=616.4 [M+Na]+。
Step 2：(R/S)-trans -3- [1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ6- [1,2] thiazan -2- ylmethyls)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxies methoxyl group)-ring fourth Base] -3- hydroxy-propionic acid ethyl esters
It is molten in -78 DEG C of THF (3.0mL) to LDA (696 μ L, 1.39mmol, 2.0M THF/ heptane/ethyl benzole solns) EtOAc (162 μ L, 1.67mmol) is added in liquid.Reactant is stirred into 0.5h in -78 DEG C, then adds the product obtained from step 1 THF (1.0mL) solution of (330mg, 0.556mmol).Reactant is stirred into 0.5h in -78 DEG C, then uses H2O (8mL) is quenched, Warm to room temperature.Mixture is extracted (20mL) with EtOAc.Organic moiety NaHCO3(sat., aq., 10mL) is washed, through sulphur Sour sodium is dry and is concentrated in vacuo.By purification by flash chromatography (0-70% EtOAc/ hexamethylenes), the target for grease is obtained Compound (310mg).LCMS(ESI)：M/z=704.5 [M+Na]+。
Step 3：(R/S)-trans -3- [1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ6- [1,2] thiazan -2- ylmethyls)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxies methoxyl group)-ring fourth Base] -3- hydroxy-propanamides
Add in MeOH (3.5mL) and THF (1.25mL) solution to the product (240mg, 0.352mmol) obtained from step 2 Enter NaOH (28mg, 0.70mmol) H2O (3.5mL) solution.Reactant is heated into 1h in 50 DEG C, room temperature is subsequently cooled to, uses EtOAc (50mL) dilutes.Mixture HCl (1M, aq., 15mL), salt solution (15mL) are washed, dried over sodium sulfate and vacuum Concentration.Crude material is dissolved in DMF (0.8mL), is then sequentially added into diisopropylethylamine (184 μ L, 1.06mmol), HATU (187mg, 0.493mmol) and NH4OH(59μL,0.53mmol).Reactant is stirred into 1h at room temperature, then uses H2O(5mL) Dilution, is extracted (20mL) with EtOAc.Organic moiety is dried over sodium sulfate and be concentrated in vacuo with salt water washing (3 × 10mL).It is logical Purification by flash chromatography (50-100% EtOAc/ hexamethylenes) is crossed, obtains the target compound (230mg) for grease.LCMS (ESI)：M/z=653.4 [M+H]+。
Step 4：(R/S)-anti-form-1-[1- [bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, 1- dioxo-6- phenyl-1 λ6- [1,2] thiazan -2- ylmethyls)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxies methoxyl group)-ring fourth Base] -2- (1H- [1,2,4] triazole -3- bases)-ethanol
The product (230mg, 0.352mmol) of step 3 be will be obtained from dimethylformamide dimethyl acetal (3.8mL) Solution heats 1.5h in 70 DEG C, is subsequently cooled to room temperature, solvent is removed in vacuum.By crude material together with toluene azeotropic, then It is dissolved in acetic acid (3.8mL) and hydrazine hydrate (191 μ L, 2.68mmol).Reactant is heated into 1.5h in 70 DEG C, is subsequently cooled to Room temperature, solvent is removed in vacuum.By purification by flash chromatography (20-90% EtOAc/ hexamethylenes), the target for grease is obtained Compound (120mg).LCMS(ESI)：M/z=677.4 [M+H]+。
Step 5：Trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1,2] Thiazan -2- ylmethyls)-phenyl] -3- [(S) -1- hydroxyls -2- (1H- [1,2,4] triazole -3- bases)-ethyl] -1- methyl-ring Butanol and trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- Ylmethyl)-phenyl] -3- [(R) -1- hydroxyls -2- (1H- [1,2,4] triazole -3- bases)-ethyl] -1- methyl-cyclobutanol
So that obtained from step 4 product (120mg, 0.220mmol) according to step 5 methods described of embodiment 12 reaction and it is pure Change, obtain solid target compound.Diastereoisomer passes through chiral SFC purifies and separates.Trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- [(S) -1- hydroxyls Base -2- (1H- [1,2,4] triazole -3- bases)-ethyl] -1- methyl-cyclobutanol1H NMR(400MHz,DMSO-d6)δ13.58- 13.45 (1H, m), 7.75 (1H, s), 7.49-7.37 (5H, m), 7.16 (1H, dd, J=6.2,11.2Hz), 6.99 (1H, dd, J =6.3,11.0Hz), 5.34-5.30 (1H, m), 4.77 (1H, s), 4.60-4.48 (2H, m), 4.37 (1H, d, J= 17.8Hz),4.17-4.11(2H,m),2.68-2.62(2H,m),2.47-2.28(4H,m),2.22-2.07(2H,m),1.86- 1.65 (2H, m), 1.31 (3H, s), 1.15 (3H, d, J=6.8Hz).LCMS(ESI)：M/z=547.3 [M+H]+.Trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-benzene Base] -3- [(R) -1- hydroxyls -2- (1H- [1,2,4] triazole -3- bases)-ethyl] -1- methyl-cyclobutanol1H NMR(400MHz, DMSO-d6) δ 13.58-13.46 (1H, m), 7.74 (1H, s), 7.49-7.37 (5H, m), 7.16 (1H, dd, J=6.1, 11.2Hz), 6.99 (1H, dd, J=6.4,11.0Hz), 5.32-5.29 (1H, m), 4.80-4.72 (1H, m), 4.60-4.48 (2H, m), 4.37 (1H, d, J=17.7Hz), 4.18-4.09 (2H, m), 2.68-2.63 (2H, m), 2.47-2.30 (4H, m), 2.21-2.06 (2H, m), 1.87-1.76 (1H, m), 1.72-1.64 (1H, m), 1.31 (3H, s), 1.15 (3H, d, J= 6.9Hz).LCMS(ESI)：M/z=547.3 [M+H]+。
Embodiment 16：(R/S)-trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ6- [1,2] thiazan -2- ylmethyls)-phenyl] -3- [2- hydroxyls -2- (1H- [1,2,4] triazole -3- bases)-ethyl] -1- first Base-cyclobutanol
Step 1：Trans-(3S, 6R) -2- { bis- fluoro- 4- of 2,5- [1- (- 2- Methoxy-vinyls) -3- methyl -3- (2- tri- Methyl-monosilane base-(ethoxymethyl) epoxide)-cyclobutyl]-benzyl } -3- methyl -6- phenyl-[1,2] thiazan 1,1- dioxide
In 0 DEG C to (methoxy) benzyltriphenylphosphonium chlorideAdded in THF (20mL) solution of (1.36g, 4.42mmol) Potassium tert-butoxide (2.95mL, 2.95mmol, 1.0M THF solution).Reactant is stirred into 0.5h in 0 DEG C, then adds 1- [2,5- Two fluoro- 4- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- first THF (5mL) solution of base -3- (2- trimethylsilyl-ethoxies methoxyl group)-cyclobutane formaldehyde (875mg, 1.47mmol). Mixture is stirred into 20min in 0 DEG C, is then quenched with salt solution (30mL), is warmed to room temperature, extracted (60mL) with EtOAc.It is organic Part is dried over sodium sulfate and is concentrated in vacuo.By purification by flash chromatography (0-60% EtOAc/ hexamethylenes), obtain as oily The target compound (774mg) of thing, it is the 60 of olefin isomer:40 mixtures.1H NMR(300MHz,CDCl3)δ7.51-7.24 (6H, m), 6.93 (0.4H, dd, J=6.2,10.8Hz), 6.75 (0.6H, dd, J=6.3,10.5Hz), 6.27 (0.6H, d, J =12.8Hz), 5.74 (0.4H, d, J=6.3Hz), 5.06 (0.6H, d, J=12.9Hz), 4.73 (0.4H, dd, J=2.0, 6.3Hz), 4.69 (2H, s), 4.51 (1H, d, J=17.1Hz), 4.38 (1H, d, J=17.1Hz), 4.32-4.20 (1H, m), 4.03-3.95(1H,m),3.64-3.55(2H,m),3.50(1.2H,s),3.49(1.8H,s),2.78-2.46(5H,m), 2.28-2.17 (1H, m), 1.83-1.72 (2H, m), 1.55 (1.2H, s), 1.53 (1.8H, s), 1.16 (3H, d, J= 6.9Hz),0.94-0.86(2H,m),0.00(9H,s).LCMS (ESI) m/z=639.7 [M+H2O]+.
Step 2：{ 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazine Alkane -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl }-acetaldehyde
HCl is added into the flask containing the product (774mg, 1.24mmol) obtained from step 1, and (4.0M dioxane is molten Liquid, 12.4mL) and HCl (2.0M, aq., 12.4mL).Reactant is stirred into 1h at room temperature, then uses NaHCO3(sat., Aq., to pH 10) neutralize.Mixture is extracted (2 × 30mL) with EtOAc, organic moiety is dried over sodium sulfate and vacuum is dense Contracting.By purification by flash chromatography (0-60% EtOAc/ hexamethylenes), the target compound (574mg) for solid is obtained.LCMS (ESI)：M/z=500.2 [M+Na]+。
Step 3：(R/S)-trans -3- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ6- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl } -2- hydroxyls-propionitrile
Trimethyl silyl is added into DCM (24mL) solution of the product (574mg, 1.20mmol) obtained from step 2 Cyanide (0.226mL, 1.80mmol) and Et3N(0.251mL,1.80mmol).Reactant is stirred into 1h at room temperature, then Use K2CO3(2.0M, aq., 20mL) is quenched, and is stirred for 0.5h.Reactant is extracted (2 × 30mL) with DCM, organic portion of merging Divide dried over sodium sulfate and be concentrated in vacuo.By crude material be dissolved in MeOH (3.0mL) and HCl (4.0M dioxane solution, 12.4mL), 0.5h is stirred, solvent is then removed in vacuum.By purification by flash chromatography (0-70% EtOAc/ hexamethylenes), obtain Obtain solid target compound (554mg).LCMS(ESI)：M/z=527.3 [M+Na]+。
Step 4：(R/S)-trans -3- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ6- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl } -2- hydroxy-propanamides
So that the product (360mg, 0.714mmol) obtained from step 3 reacts according to step 6 methods described of embodiment 9, obtain Target compound (200mg).1H NMR(400MHz,DMSO-d6)δ7.48-7.36(5H,m),7.16-7.09(2H,m),7.05- 6.96 (2H, m), 5.17 (1H, d, J=5.9Hz), 4.74 (1H, s), 4.58-4.46 (2H, m), 4.35 (1H, d, J= 17.6Hz),4.15-4.10(1H,m),2.68-2.61(1H,m),2.48-2.31(5H,m),2.14-2.07(2H,m),1.95- 1.76 (2H, m), 1.71-1.63 (1H, m), 1.31 (3H, s), 1.12 (3H, dd, J=1.5,6.8Hz). NH2notobserved.LCMS(ESI)：M/z=523.2 [M+H]+。
Step 5：(R/S)-trans -3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- [2- hydroxyls -2- (1H- [1,2,4] triazole -3- bases)-ethyl] -1- methyl-ring Butanol
So that 3 products (150mg, 0.287mmol) obtained from step react according to step 4 methods described of embodiment 15, obtain Obtain target compound (46mg).1H NMR(400MHz,DMSO-d6)δ13.70(1H,br.s),7.74(1H,br.s),7.49- 7.36(5H,m),7.17-7.10(1H,m),6.98-6.97(1H,m),5.52(1H,br.s),4.74(1H,s),4.59-4.46 (2H, m), 4.35 (1H, dd, J=3.3,17.6Hz), 4.22 (1H, br.s), 4.17-4.09 (1H, m), 2.68-2.61 (1H, m),2.48-2.39(2H,m),2.34-2.23(3H,m),2.15-2.06(2H,m),1.87-1.76(1H,m),1.71-1.63 (1H, m), 1.32 (3H, s), 1.13 (3H, d, J=6.8Hz).LCMS(ESI)：M/z=547.1 [M+H]+。
Embodiment 17：Trans-(R) -5- 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl - 1λ6- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl }-oxazolidine -2- ketone and trans-(S) - 5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls) - Phenyl] -3- hydroxy-3-methyls-cyclobutyl }-oxazolidine -2- ketone
Step 1：(R/S)-anti-form-1-[1- [bis- fluoro- 4- of 2,5- ((3S, 6R)-3- methyl isophthalic acids, 1- dioxo-6- phenyl-1 λ6- [1,2] thiazan -2- ylmethyls)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxies methoxyl group)-ring fourth Base] -2- nitros-ethanol
To 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- Ylmethyl)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxies methoxyl group)-cyclobutane formaldehyde (649mg, Diisopropylethylamine (568 μ L, 3.27mmol) is added in nitromethane (5.0mL) solution 1.09mmol).By reactant in room The lower stirring 4h of temperature, is then removed in vacuum solvent.By purification by flash chromatography (0-70% EtOAc/ hexamethylenes), it is solid to obtain The target compound (660mg) of body.LCMS(ESI)：M/z=677.4 [M+Na]+。
Step 2：(R/S)-trans -2- amino -1- [1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxos - The λ of 6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- methyl -3- (2- trimethylsilyl-ethoxy methoxies Base)-cyclobutyl]-ethanol
NH is added into IMS (2.4mL) solution of the product (200mg, 0.306mmol) obtained from step 14Cl(100mg, H 1.86mmol)2O (0.8mL) solution.Reactant is stirred vigorously, iron powder (68mg, 1.2mmol) is then added, will react Thing heats 0.5h in 85 DEG C.Reactant is cooled to room temperature, filtered by diatomite, solvent is removed in vacuum.Crude product is dissolved in EtOAc (20mL), organic matter are dried over sodium sulfate and be concentrated in vacuo with salt water washing (20mL).Crude material is dissolved in DMF (0.7mL), then add 1,1- carbonyl dimidazoles (74mg, 0.46mmol) and Et3N(64μL,0.46mmol).By reactant in 16h is stirred at room temperature, is then diluted with EtOAc (30mL).Organic moiety is dried over sodium sulfate with salt water washing (4 × 10mL) And it is concentrated in vacuo.By purification by flash chromatography (0-90% EtOAc/ hexamethylenes), the target compound for grease is obtained (152mg)。1H NMR(300MHz,CDCl3) δ 7.52-7.36 (6H, m), 6.92 (1H, dd, J=6.1,10.4Hz), 5.58 (1H, d, J=15.7Hz), 4.86 (1H, dt, J=2.5,8.1Hz), 4.68-4.65 (2H, m), 4.59-4.48 (1H, m), 4.45-4.34 (1H, m), 4.34-4.24 (1H, m), 4.03 (1H, td, J=2.9,12.9Hz), 3.58-3.47 (2H, m), 3.31-3.08 (2H, m), 2.80-2.56 (5H, m), 2.31-2.20 (1H, m), 1.85-1.73 (2H, m), 1.53 (3H, d, J= 2.2Hz), 1.18 (3H, t, J=6.3Hz), 0.93-0.83 (2H, m), 0.02--0.01 (9H, m).LCMS(ESI)：M/z= 673.3[M+Na]+。
Step 3：Trans-(R) -5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl -1 λ6- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl }-oxazolidine -2- ketone and trans-(S) -5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-benzene Base] -3- hydroxy-3-methyls-cyclobutyl }-oxazolidine -2- ketone
HCl (the two of 4.0M are added into MeOH (2.0mL) solution of the product (152mg, 0.234mmol) obtained from step 2 The ring solution of oxygen six, 2.0mL).Reactant is stirred into 0.5h, solvent is then removed in vacuum.Crude product is dissolved in EtOAc (20mL), had Machine part NaHCO3(sat., aq., 15mL) is washed, dried over sodium sulfate and be concentrated in vacuo.Diastereoisomer passes through chirality SFC purifies and separates.Trans-(R) -5- { 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl }-oxazolidine -2- ketone1H NMR(400MHz, DMSO-d6) δ 7.48-7.35 (6H, m), 7.17 (2H, ddd, J=6.3,11.3,13.3Hz), 4.89 (1H, s), 4.79-4.73 (1H, m), 4.59-4.47 (2H, m), 4.36 (1H, d, J=17.7Hz), 4.14-4.07 (1H, m), 3.30-3.26 (1H, m), 3.02 (1H, dd, J=7.1,8.7Hz), 2.49-2.45 (3H, m), 2.44-2.32 (2H, m), 2.14-2.06 (1H, m), 1.86-1.74 (1H, m), 1.67 (1H, dd, J=2.0,14.2Hz), 1.30 (3H, s), 1.12 (3H, d, J=6.8Hz).LCMS (ESI)：M/z=521.2 [M+H]+.Trans-(S) -5- 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxos - The λ of 6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- hydroxy-3-methyls-cyclobutyl }-oxazolidine -2- ketone1H NMR (400MHz,DMSO-d6) δ 7.48-7.35 (6H, m), 7.22-7.13 (2H, m), 4.89 (1H, s), 4.75 (1H, dd, J= ), 6.6,8.8Hz 4.59-4.47 (2H, m), 4.36 (1H, d, J=17.8Hz), 4.13 (1H, ddd, J=2.0,6.9, 11.8Hz), 3.30-3.25 (1H, m), 3.01 (1H, dd, J=6.9,8.7Hz), 2.57-2.52 (1H, m), 2.48-2.34 (4H, m), 2.14-2.06 (1H, m), 1.87-1.75 (1H, m), 1.67 (1H, dd, J=2.2,14.2Hz), 1.31 (3H, s), 1.12 (3H, d, J=6.8Hz).LCMS(ESI)：M/z=521.2 [M+H]+。
Embodiment 18：Trans-N- [3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- ylmethyls)-phenyl] -1- methyl -3- (5- oxo -4,5- dihydros-[and 1,3,4] oxadiazole -2- bases)-ring Butyl]-acetamide
Step 1：Trans -3- acetyl-aminos -1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- benzene The λ of base -16- [1,2] thiazan -2- ylmethyls)-phenyl] -3- methyl-cyclobutane formate methyl esters
To 1- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16- [1,2] thiazan -2- Ylmethyl)-phenyl] -3- hydroxy-3-methyls-cyclobutane formate methyl esters (500mg, 1.01mmol) MeCN (20mL) solution in Add H2SO4(conc.,200μL).Reactant is stirred into 1h in 50 DEG C, then uses H2O (5mL) is quenched, and is extracted with EtOAc (100mL).Organic layer H2O(70mL)、NaHCO3(sat., aq., 30mL) is washed, dried over sodium sulfate and be concentrated in vacuo.With Et2O is ground, and obtains the target compound (400mg) for solid.1H NMR(400MHz,DMSO-d6)δ7.92(1H,s),7.48- 7.36 (5H, m), 7.22-7.15 (2H, m), 4.60-4.48 (2H, m), 4.37 (1H, d, J=17.8Hz), 4.15-4.08 (1H, m),3.59(3H,s),2.80(4H,s),2.48-2.38(1H,m),2.14-2.06(1H,m),1.81-1.75(1H,m),1.67 (4H, s), 1.38 (3H, s), 1.13 (3H, d, J=6.9Hz).LCMS(ESI)：M/z=535.2 [M+H]+,
Step 2：Trans-N- [3- [bis- fluoro- 4- of 2,5- ((3S, 6R) -3- methyl isophthalic acids, the λ of 1- dioxo -6- phenyl -16-[1, 2] thiazan -2- ylmethyls)-phenyl] -1- methyl -3- (5- oxo -4,5- dihydros-[and 1,3,4] oxadiazole -2- bases)-ring fourth Base]-acetamide
So that the product (300mg, 0.561mmol) obtained from step 1 reacts according to step 5 methods described of embodiment 10, obtain Obtain solid target compound.1H NMR(400MHz,DMSO-d6)δ12.25(1H,s),7.96(1H,s),7.48-7.36(5H, M), 7.27-7.19 (2H, m), 4.60-4.49 (2H, m), 4.37 (1H, d, J=17.8Hz), 4.17-4.09 (1H, m), 3.01- 2.86(4H,m),2.48-2.38(1H,m),2.14-2.06(1H,m),1.86-1.75(1H,m),1.68-1.62(4H,m), 1.39 (3H, s), 1.13 (3H, d, J=6.9Hz).LCMS(ESI)：M/z=561.2 [M+H]+。
Embodiment 19：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl - 1,2- thiazan -2- bases) methyl) phenyl) -2 (3H) -one of -3- hydroxy-3-methyl cyclobutyl) oxazoles
Step 1：3- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl) -3- propionic acid methyl esters
1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazine are added into round-bottomed flask Alkane -2- bases) methyl) phenyl) -3- hydroxy-3-methyls-cyclobutane formate (550mg, 1.15mmol) and tetrahydrofuran (10mL), 1,1'- carbonyl dimidazoles (199mg, 1.20mmol) are then added, reactant are stirred at room temperature 2 hours.Add magnesium chloride (126mg, 1.32mmol) and 3- methoxyl group -3- oxopropanoic acids potassium (210mg, 1.32mmol), 50 DEG C are heated to by reactant, in Stirred 16 hours at a temperature of this.Then reactant mixture is filtered, in evaporated onto silica gel, passes through silica gel chromatography (i- PrOAc 0-100%/heptane), obtain the target compound (454mg) for white solid.LCMS ES+536.1[M+1]+。
Step 2：3- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl)-N- hydroxyl -3- oxopropanamides
Into round-bottomed flask add 3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxo -6- phenyl - Thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls-cyclobutyl) -3- oxo-propionic acid methyl esters (266mg, 0.50mmol) With methanol (3mL), the solution of acquisition is cooled to -30 DEG C.Sodium hydroxide is added into the solution of cooling, and (0.25M MeOH is molten Liquid, 2.2mL), reactant is stirred 10 minutes in -30 DEG C.Hydroxylamine hydrochloride (86mg, 1.24mmol) is added into the solution in hydrogen Solution (0.25M MeOH solution, 5.0mL) and water (1mL) in sodium oxide molybdena.The mixture of acquisition is stirred 10 points in -30 DEG C Clock, then in -25 DEG C of agings 16 hours in refrigerator.The aqueous ammonium chloride solution (20mL) of reactant saturation is diluted, uses i- PrOAc (3 × 5mL) and CH2Cl2(10mL) is extracted, dried over magnesium sulfate, concentration, passes through silica gel chromatography (MeOH 0- 30%/CH2Cl2), obtain the target compound (140mg) for white solid.LCMS ES+537.1[M+1]+.
Step 3：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -2 (3H) -one of -3- hydroxy-3-methyl cyclobutyl) oxazoles
By 3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases) first Base) phenyl) -3- hydroxy-3-methyls-cyclobutyl) and -3- xo-propanes hydroxamic acid (372mg, 0.69mmol) tetrahydrofuran (7mL) solution is cooled to 0 DEG C.N is added, N- diisopropyl ethyl amines (0.31mL, 1.7mmol), then adds 4- nitrobenzene sulphurs Acyl chlorides (188mg, 0.76mmol).By reactant in 0 DEG C to being stirred at room temperature 16 hours.By the chlorination of the mixture saturation of acquisition Aqueous ammonium (20mL) is quenched, and uses CH2Cl2(3 × 10mL) is extracted, dried over magnesium sulfate, concentration, passes through reverse phase preparative HPLC Purify (aqueous formic acid of acetonitrile 20-60%/0.1%), obtain target compound (30mg).1H NMR(400MHz,DMSO- d6)δ10.39(s,1H),7.51–7.43(m,2H),7.43–7.33(m,3H),7.23–7.05(m,2H),6.82(s,1H), 5.06 (s, 1H), 4.56 (dd, J=12.6,3.5Hz, 1H), 4.50 (d, J=17.7Hz, 1H), 4.35 (d, J=17.9Hz, 1H), 4.20-4.03 (m, 1H), 2.72 (d, J=13.0 Hz, 2H), 2.57 (d, J=12.6 Hz, 2H), 2.47-2.36 (m, 1H), 2.15-2.06 (m, 1H), 1.89-1.72 (m, 1H), 1.72-1.61 (m, 1H), 1.26 (s, 3H), 1.12 (d, J=6.8 Hz,3H)；LCMS ES+519.2[M+1]+。
Embodiment 20：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl - 1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl) -2 (3H) -one of -3- Jia Ji oxazoles
At room temperature, to 5- (1- (2,5- bis- fluoro- 4- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazine Alkane -2- bases) methyl) phenyl) -3- hydroxy-3-methyls-cyclobutyl) -3H- oxazole -2- ketone (15mg, 0.029mmol) N, N- bis- Potassium carbonate (14.0mg, 0.174mmol) is added in NMF (0.5 mL) solution, reactant is stirred 2 minutes.Then plus Enter iodomethane (0.086mL, 0.054mmol), reactant is stirred at room temperature 2 hours.The mixture of acquisition is passed throughFiltering, concentration.(aqueous formic acid of acetonitrile 20-60%/0.1%) is purified by reverse phase preparative HPLC, obtained It must be the target compound (11.6 mg) of white solid.1H NMR(400 MHz,DMSO-d6)δ7.49–7.43(m,2H), 7.43-7.35 (m, 3H), 7.15 (ddd, J=19.5,10.8,6.3 Hz, 2H), 6.90 (s, 1H), 5.08 (s, 1H), 4.56 (dd, J=12.9,3.5 Hz, 1H), 4.50 (d, J=18.0 Hz, 1H), 4.35 (d, J=17.6 Hz, 1H), 4.19-4.02 (m, 1H), 3.05 (s, 3H), 2.71 (d, J=13.0Hz, 2H), 2.59 (d, J=12.9 Hz, 2H), 2.47-2.38 (m, 1H), 2.16-2.05 (m, 1H), 1.86-1.72 (m, 1H), 1.71-1.61 (m, 1H), 1.27 (s, 3H), 1.13 (d, J=6.9 Hz, 3H)；LCMS ES+533.2[M+1]+。
Embodiment 21：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl - 1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl) -2 (3H) -one of -4- Jia Ji oxazoles
Step 1：3- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl) -2- methyl -3- propionic acid methyl esters
To 3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases) first Base) phenyl) -3- hydroxy-3-methyls-cyclobutyl) and -3- oxo-propionic acid methyl esters (490mg, 0.91mmol) N, N- dimethyl methyls Cesium carbonate (656mg, 2.0mmol) is added in acid amides (4.5mL) solution, reactant is stirred at room temperature 10 minutes.Then plus Enter iodomethane (0.06mL, 1.0mmol), reactant is stirred at room temperature 16 hours.By the chlorine of the mixture saturation of acquisition Change aqueous ammonium (10mL) quenching, adjusted pH to 1 using concentrated hydrochloric acid.Product CH2Cl2(3 × 10mL) is extracted, through magnesium sulfate Dry, concentration, by silica gel chromatography (i-PrOAc 0-100%/heptane), obtain the target chemical combination for white solid Thing (378mg).LCMS ES+550.1[M+1]+。
Step 2：3- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl)-N- hydroxy-2-methyl -3- oxopropanamides
Into round-bottomed flask add 3- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxides - 6- phenyl -1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl) -2- methyl -3- propionic acid methyl esters (378mg, 0.69mmol) and methanol (3mL), -30 DEG C are cooled to by the solution of acquisition.Hydroxide is added into the solution of cooling Sodium (0.25M MeOH solution, 3.0mL), reactant is stirred 10 minutes in -30 DEG C.Then hydrochloric acid hydroxyl is added into the solution Solution (0.25M MeOH solution, 6.9mL) and water (0.5mL) of the amine (124mg, 1.7mmol) in sodium hydroxide.It will obtain Mixture stirred in -30 DEG C 10 minutes, then in -25 DEG C of agings 16 hours in refrigerator.By the chlorination of reactant saturation Aqueous ammonium (10mL) dilutes, with i-PrOAc (3 × 5mL) and CH2Cl2(5mL) is extracted, dried over magnesium sulfate, concentration, passes through silicon Glue column chromatography purifies (MeOH 0-30%/CH2Cl2), obtains the target compound (153mg) for white solid.LCMS ES+ 551.1[M+1]+。
Step 3：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl) -2 (3H) -one of -4- Jia Ji oxazoles
By 3- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiophenes Piperazine alkane -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl)-N- hydroxy-2-methyl -3- oxopropanamides (153mg, Tetrahydrofuran (3.0mL) solution 0.83mmol) is cooled to 0 DEG C.Addition N, N- diisopropylethylamine (0.12mL, 0.69mmol), 4- nitrobenzene sulfonyl chlorides (75mg, 0.31mmol) are then added, reactant is small to being stirred at room temperature 16 in 0 DEG C When.The aqueous ammonium chloride solution (10mL) of the mixture saturation of acquisition is quenched, uses CH2Cl2(3 × 5mL) is extracted, through magnesium sulfate Dry, concentration, (aqueous formic acid of acetonitrile 20-60%/0.1%) is purified by reverse phase preparative HPLC, obtain as white admittedly The target compound (13.8mg) of body.1H NMR(400MHz,DMSO-d6)δ7.50–7.43(m,2H),7.43–7.33(m,3H), 7.30-7.21 (m, 1H), 7.15 (dd, J=11.2,6.1Hz, 1H), 5.00 (s, 1H), 4.61-4.46 (m, 2H), 4.35 (d, J =17.9Hz, 1H), 4.18-4.04 (m, 1H), 2.98-2.88 (m, 2H), 2.66-2.57 (m, 2H), 2.46-2.36 (m, 1H), 2.16–2.05(m,1H),1.88–1.72(m,1H),1.71–1.60(m,1H),1.43(s,3H),1.18(s,3H),1.11(d, J=6.8Hz, 3H)；LCMS ES+533.2[M+1]+。
Embodiment 21 and 22：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxides -6- Phenyl -1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl) (2H) -one of -2- methyl-isoxazoles -3 and (3S, 6R) -2- (bis- fluoro- 4- of 2,5- ((1R, 3S) -3- hydroxyls -1- (3- first epoxides isoxazole -5-base) -3- methyl-cyclobutyls) benzyls Base) -3- methyl -6- phenyl -1,2- thiazan 1,1- dioxide
Step 1：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -3 (2H) -one of -3- hydroxy-3-methyl cyclobutyl) isoxazoles
To containing 4- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases) first Base) phenyl) -3- oxos-pentane hydroxamic acid (500mg, 0.93mmol) round-bottomed flask in add methanol (5mL) and concentrated hydrochloric acid The aqueous solution (1.5mL).Reactant is stirred 2 hours in 80 DEG C.The mixture of acquisition is cooled to room temperature, it is dilute with water (20mL) Release, with i-PrOAc (3 × 5mL) and CH2Cl2(10mL) is extracted, dried over magnesium sulfate, and (second is purified by reverse phase preparative HPLC The aqueous formic acid of nitrile 20-60%/0.1%), obtain target compound (213mg).LCMS ES+519.1[M+1]+。
Step 2：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl) (2H) -one of -2- methyl-isoxazoles -3 and (3S, 6R) - 2- (bis- fluoro- 4- of 2,5- ((1R, 3S) -3- hydroxyls -1- (3- first epoxides isoxazole -5-base) -3- methyl-cyclobutyls) benzyl) -3- first Base -6- phenyl -1,2- thiazan 1,1- dioxide
At room temperature, to 5- (1- (2,5- bis- fluoro- 4- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazine Alkane -2- bases) methyl) phenyl) and -3- hydroxy-3-methyls-cyclobutyl) isoxazole -3- ketone (213mg, 0.41mmol) methanol In (1.5m) and tetrahydrofuran (1.5m) solution be added dropwise (trimethyl silyl) diazomethane (2.0M hexane solution ,~ 1.0mL), until yellow continues more than 10 seconds.Reactant is stirred at room temperature 30 minutes.By the mixture saturation of acquisition Aqueous ammonium chloride solution (20mL) quenching, use CH2Cl2(3 × 10mL) is extracted, dried over magnesium sulfate, concentration, passes through anti-phase preparation Property HPLC purifying (aqueous formic acid of acetonitrile 20-60%/0.1%), obtain target compound.
For 5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, the 1- titanium dioxide -6- benzene of white solid Base -1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxy-3-methyls cyclobutyl) -2- methyl-isoxazoles -3 (2H) -one (68mg)。1H NMR(400MHz,DMSO-d6)δ7.49–7.43(m,2H),7.43–7.33(m,3H),7.27–7.17(m,2H), 5.17 (s, 1H), 4.57 (dd, J=12.8,3.4Hz, 1H), 4.51 (d, J=17.9Hz, 1H), 4.36 (d, J=18.0Hz, 1H),4.19–4.06(m,1H),3.30(s,3H),2.94–2.83(m,2H),2.76–2.63(m,2H),2.15–2.06(m, 1H), 1.88-1.71 (m, 1H), 1.71-1.62 (m, 1H), 1.24 (s, 3H), 1.13 (d, J=6.9Hz, 3H)；LCMS ES+ 533.2[M+1]+。
For white solid (3S, 6R) -2- (bis- fluoro- 4- of 2,5- ((1R, 3S) -3- hydroxyls -1- (3- first epoxides isoxazole - 5- yls) -3- methyl-cyclobutyls) benzyl) -3- methyl -6- phenyl -1,2- thiazan 1,1- dioxide (56mg).1H NMR (400MHz,DMSO-d6) δ 7.50-7.43 (m, 2H), 7.43-7.33 (m, 3H), 7.23 (dd, J=10.5,6.4Hz, 1H), 7.18 (dd, J=11.0,6.2Hz, 1H), 6.22 (s, 1H), 5.14 (s, 1H), 4.56 (dd, J=12.6,3.6Hz, 1H), 4.50 (d, J=17.8Hz, 1H), 4.35 (d, J=17.7Hz, 1H), 4.20-4.04 (m, 1H), 3.82 (s, 3H), 2.95- 2.85(m,2H),2.77–2.69(m,2H),2.47–2.36(m,1H),2.15–2.07(m,1H),1.88–1.72(m,1H), 1.71-1.61 (m, 1H), 1.18 (s, 3H), 1.12 (d, J=6.9Hz, 3H)；LCMS ES+533.2[M+1]+。
Embodiment 23：(S) -5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxides -6- Phenyl -1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxycyclobutyl) oxazolidine -2- ketone：
Step 1：1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) -3- oxo cyclobutane -1- formic acid
To 1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- bases) methyl) Phenyl) in the tetrahydrofuran (90mL) of -3- oxos-cyclobutane formate methyl esters (12.1g, 25.3mmol) and the solution of water (30mL) Lithium hydroxide (10.9g, 253mmol) is added, reactant is stirred at room temperature 4 hours.By the mixture water of acquisition (200mL) dilutes, and is adjusted pH to 1 using concentrated hydrochloric acid aqueous solution.Then reactant mixture with i-PrOAc (2 × 100mL) and CH2Cl2(50mL) is extracted, dried over magnesium sulfate, concentration, obtains target compound (9.2g).LCMS ES+464.1[M+1]+。
Step 2：1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) -3- hydroxycyclobutane -1- formic acid
At room temperature, to 1- (2,5- bis- fluoro- 4- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxos -6- phenyl-thiazan -2- Base) methyl) phenyl) and -3- oxos-cyclobutane formate (1.0g, 2.1mmol) ethanol (11mL) solution in add sodium borohydride (250mg,6.47mmol).Gas overflowing simultaneously lasts about 5 minutes.Reactant is stirred at room temperature 30 minutes.What is obtained is mixed For compound by the way that concentrated hydrochloric acid aqueous solution quenching is added dropwise until gas overflowing stops, white suspension becomes uniform solution.By solution Diluted with water (100mL), cause white precipitate to produce, use CH2Cl2With the 10 of MeOH:1 mixture extracts (5 × 25mL), through sulphur Sour magnesium is dried, and concentration, passes through silica gel chromatography (MeOH 0-30%/CH2Cl2), obtain the target chemical combination for white solid Thing (640mg).LCMS ES+466.1[M+1]+.
Step 3：3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) -3- hydroxycyclobutyls) -3- propionic acid methyl esters
1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- are added into round-bottomed flask Thiazan -2- bases) methyl) phenyl) -3- hydroxycyclobutane -1- formic acid (630mg, 1.35mmol) and tetrahydrofuran (10mL), with After add 1,1'- carbonyl dimidazoles (235mg, 1.42mmol), reactant is stirred at room temperature 2 hours.Add magnesium chloride (148mg, 1.55mmol) and 3- methoxyl group -3- oxopropanoic acids potassium (248mg, 1.55mmol), 50 DEG C are heated to by reactant, in Stirred 16 hours at a temperature of this.Then reactant mixture is filtered, in evaporated onto silica gel, passes through silica gel chromatography (i- PrOAc0-100%/heptane), obtain the target compound (241mg) for white solid.LCMS ES+522.1[M+1]+。
Step 4：3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) -3- hydroxycyclobutyls)-N- hydroxyl -3- oxopropanamides
Into round-bottomed flask add 3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl - 1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxycyclobutyls) -3- propionic acid methyl esters (240mg, 0.46mmol) and methanol (3mL), the solution of acquisition is cooled to -30 DEG C.Into the solution of cooling add sodium hydroxide (0.25M MeOH solution, 2.0mL), reactant is stirred 10 minutes in -30 DEG C.Then hydroxylamine hydrochloride (83mg, 1.15mmol) is added into the solution The solution of sodium hydroxide (0.25M MeOH solution, 4.6mL) and water (1mL).The mixture of acquisition is stirred 10 points in -30 DEG C Clock, then in -25 DEG C of agings 16 hours in refrigerator.The aqueous ammonium chloride solution (20mL) of reactant saturation is diluted, uses i- PrOAc (3 × 5mL) and CH2Cl2(10mL) is extracted, dried over magnesium sulfate, concentration, passes through silica gel chromatography (MeOH 0- 30%/CH2Cl2), obtain the target compound (122mg) for white solid.LCMS ES+523.1[M+1]+。
Step 5：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -2 (3H) -one of -3- hydroxycyclobutyl) oxazoles
By 3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) -3- hydroxycyclobutyls)-N- hydroxyl -3- oxopropanamides (122mg, 0.23mmol) tetrahydrofuran (2.5mL) solution is cooled to 0 DEG C.DIPEA (0.10mL, 0.58mmol) is added, then adds 4- nitrobenzene sulphurs Acyl chlorides (63mg, 0.25mmol), by reactant in 0 DEG C to being stirred at room temperature 16 hours.The mixture of acquisition uses the chlorination of saturation Aqueous ammonium (10mL) is quenched, and uses CH2Cl2(3 × 5mL) is extracted, dried over magnesium sulfate, concentration, passes through chiral shooting flow body colour Spectrum purifying, obtains target compound, is single diastereoisomer (12.1mg).
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),7.49–7.44(m,2H),7.43–7.35(m,3H), 7.17 (dd, J=11.0,6.1Hz, 1H), 7.07 (dd, J=10.3,6.3Hz, 1H), 6.76 (s, 1H), 5.20 (d, J= 7.1Hz, 1H), 4.56 (dd, J=12.6,3.5Hz, 1H), 4.50 (d, J=17.9Hz, 1H), 4.35 (d, J=17.9Hz, 1H),4.28–4.06(m,2H),2.97–2.86(m,2H),2.47–2.40(m,1H),2.33–2.23(m,2H),2.15–2.07 (m, 1H), 1.88-1.73 (m, 1H), 1.71-1.62 (m, 1H), 1.12 (d, J=7.0Hz, 3H)；LCMS ES+505.2[M+1 ]+。
Embodiment 24：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl - 1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxyl -3- ethene tetramethylcyclobutyl) oxazole -2 (3H) -one
Step 1：1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) -3- hydroxyl -3- vinyl cyclobutane -1- methyl formates
By 1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) -3- oxo cyclobutane -1- methyl formates (10.0g, 20.9mmol) are in methyl phenyl ethers anisole (300mL) and tetrahydrofuran Solution in (100mL) is cooled to -30 DEG C.Then vinyl magnesium bromide (1.0M THF solution, 52mL) is added dropwise, by reactant Stirred 60 minutes in -30 DEG C.The mixture of acquisition is quenched using the aqueous ammonium chloride solution (200mL) of saturation, product i-PrOAc (3 × 5 0mL) and CH2Cl2(50mL) is extracted, dried over magnesium sulfate, concentration, passes through silica gel chromatography (i-PrOAc 30- 60%/heptane), obtain the target compound (8.3g) for white solid.LCMS ES+506.1[M+1]+。
Step 2：1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) -3- hydroxyl -3- vinyl cyclobutane -1- formic acid
To 1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) -3- hydroxyl -3- vinyl cyclobutane -1- methyl formates (8.3g, 16mmol) tetrahydrofuran (100mL) and water Lithium hydroxide (14.0g, 330mmol) is added in the solution of (30mL), reactant is stirred 16 hours in 60 DEG C.By the mixed of acquisition Compound is diluted with more water (100mL), is adjusted pH to 1 using concentrated hydrochloric acid aqueous solution.Product CH2Cl2(3 × 5 0mL) extracts Take, it is dried over magnesium sulfate, concentration, obtain target compound (8.1g).LCMS ES+592.1[M+1]+。
Step 3：3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) -3- hydroxyl -3- ethene tetramethylcyclobutyl) -3- propionic acid methyl esters
1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- are added into round-bottomed flask Thiazan -2- bases) methyl) phenyl) -3- hydroxyl -3- vinyl cyclobutane -1- formic acid (8.1g, 16.6mmol) and tetrahydrofuran (55mL), 1,1'- carbonyl dimidazoles (2.88g, 17.4mmol) are then added, reactant are stirred at room temperature 5 hours.Add Magnesium chloride (18.1g, 19.0mmol) and 3- methoxyl group -3- oxopropanoic acids potassium (3.03g, 19.0mmol), reactant is heated to 50 DEG C, stirred 16 hours at a temperature of this.Then reactant mixture is filtered, in evaporated onto silica gel, passes through silica gel chromatography (i-PrOAc0-100%/heptane), obtain the target compound (2.59g) for white solid.LCMS ES+548.1[M+1]+。
Step 4：3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) -3- hydroxyl -3- ethene tetramethylcyclobutyl)-N- hydroxyl -3- oxopropanamides
Into round-bottomed flask add 3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl - 1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxyl -3- ethene tetramethylcyclobutyl) -3- propionic acid methyl esters (2.59g, 4.73mmol) and methanol (25mL), the solution of acquisition is cooled to -30 DEG C.Sodium hydroxide is added into the solution of cooling (0.25M MeOH solution, 21mL), reactant is stirred 10 minutes in -30 DEG C.Then hydroxylamine hydrochloride is added into the solution The sodium hydroxide (0.25M MeOH solution, 47mL) of (856mg, 11.8mmol) and the solution of water (5mL).By the mixing of acquisition Thing stirs 10 minutes in -30 DEG C, then in -25 DEG C of agings 16 hours in refrigerator.By the ammonium chloride solution of reactant saturation Liquid (100mL) dilutes, with i-PrOAc (3 × 20mL) and CH2Cl2(50mL) is extracted, dried over magnesium sulfate, concentration, passes through silica gel Column chromatography purifies (MeOH 0-30%/CH2Cl2), obtain the target compound (1.81g) for white solid.LCMS ES+ 549.1[M+1]+。
Step 5：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -3- hydroxyl -3- ethene tetramethylcyclobutyl) oxazole -2 (3H) -one
By 3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) -3- hydroxyl -3- ethene tetramethylcyclobutyl)-N- hydroxyl -3- oxopropanamides (1.81g, 3.30mmol) four Hydrogen furans (17mL) solution is cooled to 0 DEG C.DIPEA (1.45mL, 8.25mmol) is added, then adds 4- nitre Base benzene sulfonyl chloride (894mg, 3.63mmol), by reactant in 0 DEG C to being stirred at room temperature 16 hours.The mixture of acquisition uses saturation Aqueous ammonium chloride solution (75mL) quenching, use CH2Cl2(3 × 25mL) is extracted, dried over magnesium sulfate, concentration, is faced by the way that chirality is super Boundary's Fluid Chromatography purifying, obtains target compound, is single diastereoisomer (829mg).1HNMR(400MHz,DMSO-d6)δ 10.38(s,1H),7.51–7.43(m,2H),7.43–7.32(m,3H),7.25–7.09(m,2H),6.75(s,1H),6.03 (dd, J=17.3,10.7Hz, 1H), 5.34 (s, 1H), 5.17 (dd, J=17.1,1.9Hz, 1H), 4.97 (dd, J=10.6, 1.9Hz, 1H), 4.62-4.45 (m, 2H), 4.36 (d, J=17.7Hz, 1H), 4.22-4.02 (m, 1H), 2.96-2.86 (m, 2H),2.71–2.61(m,2H),2.47–2.37(m,1H),2.18–2.07(m,1H),1.88–1.73(m,1H),1.72–1.60 (m, 1H), 1.13 (d, J=6.9Hz, 3H)；LCMS ES+531.2[M+1]+。
Embodiment 25：5- ((1R, 3S) -3- cyclopropyl -1- (2,5- bis- fluoro- 4- (((3S, 6R) -3- methyl isophthalic acids, 1- dioxies Change -6- phenyl -1,2- thiazan -2- bases) methyl) phenyl) -2 (3H) -one of -3- hydroxycyclobutyl) oxazoles
Diethyl zinc (1.0M hexane solution, 7.1mL, 7.1mmol) is added into anhydrous CH2Cl2In (10mL), by solution It is cooled to 0 DEG C.By trifluoroacetic acid (0.55mL, 7.1mmol) CH2Cl2(10mL) solution is added dropwise in the diethyl zinc solution, The mixture of acquisition is stirred 20 minutes in 0 DEG C.Then the CH of diiodomethane (0.58mL, 7.1mmol) is added2Cl2(10mL) is molten Liquid, reactant is stirred for 20 minutes in 0 DEG C.Then by 5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl - 1,1- titanium dioxide -6- phenyl -1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxyl -3- ethene tetramethylcyclobutyl) oxazole -2 (3H) -one (750mg, 1.41mmol) is dissolved in CH2Cl2(10mL), adds to CF3CO2ZnCH2In I solution.By the solution of acquisition in room Temperature stirring 30 minutes, then it is quenched using the aqueous ammonium chloride solution (75mL) of saturation, uses CH2Cl2(3 × 25mL) is extracted, through sulfuric acid Magnesium is dried, concentration, is purified (aqueous formic acid of acetonitrile 20-60%/0.1%) by reverse phase preparative HPLC, is obtained as white The target compound (301mg) of solid.
1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),7.51–7.43(m,2H),7.43–7.31(m,3H), 7.23-7.11 (m, 2H), 6.74 (s, 1H), 4.62-4.46 (m, 2H), 4.36 (d, J=17.7Hz, 1H), 4.23-4.03 (m, 1H), 2.73 (d, J=13.1Hz, 2H), 2.55 (d, J=12.1Hz, 2H), 2.45-2.35 (m, 1H), 2.18-2.03 (m, 1H), 1.87-1.71 (m, 1H), 1.71-1.59 (m, 1H), 1.13 (d, J=6.7Hz, 3H), 1.05 (p, J=6.9Hz, 1H), 0.35–0.20(m,4H)；LCMS ES+545.1[M+1]+.
Embodiment 26：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl - 1,2- thiazan -2- bases) methyl) phenyl) -2 (3H) -one of -3- hydroxyls -3- (1- methylcyclopropyl groups) cyclobutyl) oxazoles
Step 1：1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) -3- hydroxyls -3- (propyl- 1- alkene -2- bases) cyclobutane -1- methyl formates
By 1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) -3- oxo cyclobutane -1- methyl formates (3.62g, 7.58mmol) are in methyl phenyl ethers anisole (100mL) and tetrahydrofuran Solution in (30mL) is cooled to -30 DEG C.Then isopropenyl magnesium bromide (0.55M THF solution, 34mL) is added dropwise, will react Thing stirs 60 minutes in -30 DEG C.The mixture of acquisition is quenched using the aqueous ammonium chloride solution (200mL) of saturation, product i- PrOAc (3 × 5 0mL) and CH2Cl2(50mL) is extracted, dried over magnesium sulfate, concentration, passes through silica gel chromatography (i- PrOAc30-60%/heptane), obtain the target compound (2.29g) for white solid.LCMS ES+520.1[M+1]+。
Step 2：1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) -3- hydroxyls -3- (propyl- 1- alkene -2- bases) cyclobutane -1- formic acid
To 1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazan -2- bases) first Base) phenyl) -3- hydroxyls -3- (propyl- 1- alkene -2- bases) cyclobutane -1- methyl formates (2.29g, 4.41mmol) are in tetrahydrofuran Lithium hydroxide (3.78g, 88.1mmol) is added in solution in (50mL) and water (15mL), reactant is small in 60 DEG C of stirrings 16 When.The mixture of acquisition is diluted with more water (100mL), adjusted pH to 1 using concentrated hydrochloric acid aqueous solution.Product uses CH2Cl2(3 × 5 0mL) is extracted, dried over magnesium sulfate, concentration, obtains target compound (2.2g).LCMS ES+506.1[M+1 ]+。
Step 3：3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) -3- hydroxyls -3- (propyl- 1- alkene -2- bases) cyclobutyl) -3- propionic acid methyl esters
1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- are added into round-bottomed flask Thiazan -2- bases) methyl) phenyl) -3- hydroxyls -3- (propyl- 1- alkene -2- bases) cyclobutane -1- formic acid (2.2g, 4.4mmol) and four Hydrogen furans (50mL), then adds 1,1'- carbonyl dimidazoles (756mg, 4.6mmol), and it is small that reactant is stirred to 5 at room temperature When.Add magnesium chloride (476mg, 5.0mmol) and 3- methoxyl group -3- oxopropanoic acids potassium (797mg, 5.0mmol), by reactant plus Heat stirs 16 hours to 50 DEG C at a temperature of this.Then reactant mixture is filtered, in evaporated onto silica gel, passes through silica gel column chromatography Purify (i-PrOAc0-100%/heptane), obtain the target compound (890mg) for white solid.LCMS ES+562.1[M+ 1]+。
Step 4：3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) -3- hydroxyls -3- (propyl- 1- alkene -2- bases) cyclobutyl)-N- hydroxyl -3- oxopropanamides
Into round-bottomed flask add 3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl - 1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxyls -3- (propyl- 1- alkene -2- bases) cyclobutyl) -3- propionic acid methyl esters (890mg, 1.58mmol) and methanol (10mL), -30 DEG C are cooled to by the solution of acquisition.Hydroxide is added into the solution of cooling Sodium (0.25M MeOH solution, 7.0mL), reactant is stirred 10 minutes in -30 DEG C.Then hydrochloric acid hydroxyl is added into the solution The sodium hydroxide (0.25M MeOH solution, 16mL) of amine (287mg, 3.96mmol) and the solution of water (2mL).By the mixed of acquisition Compound stirs 10 minutes in -30 DEG C, then in -25 DEG C of agings 16 hours in refrigerator.By the ammonium chloride water of reactant saturation Solution (50mL) dilutes, with i-PrOAc (3 × 10mL) and CH2Cl2(20mL) is extracted, dried over magnesium sulfate, concentration, passes through silica gel Column chromatography purifies (MeOH 0-30%/CH2Cl2), obtain the target compound (424mg) for white solid.LCMS ES+ 563.1[M+1]+。
Step 5：5- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans - 2- yls) methyl) phenyl) -3- hydroxyls -3- (propyl- 1- alkene -2- bases) cyclobutyl) oxazoles -2 (3H) -one
By 3- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1,2- thiazans -2- Base) methyl) phenyl) -3- hydroxyls -3- (propyl- 1- alkene -2- bases) cyclobutyl)-N- hydroxyl -3- oxopropanamides (424mg, Tetrahydrofuran (4mL) solution 0.75mmol) is cooled to 0 DEG C.DIPEA (0.33mL, 1.88mmol) is added, 4- nitrobenzene sulfonyl chlorides (204mg, 0.83mmol) are then added, by reactant in 0 DEG C to being stirred at room temperature 16 hours.What is obtained is mixed Compound is quenched using the aqueous ammonium chloride solution (50mL) of saturation, uses CH2Cl2(3 × 15mL) is extracted, dried over magnesium sulfate, concentration, Pass through silica gel chromatography (MeOH 0-30%/CH2Cl2), obtain the target compound (174mg) for white solid.LCMS ES+545.1[M+1]+。
Step 6：5- ((1R, 3S) -1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxide -6- phenyl -1, 2- thiazan -2- bases) methyl) phenyl) -2 (3H) -one of -3- hydroxyls -3- (1- methylcyclopropyl groups) cyclobutyl) oxazoles
Diethyl zinc (1.0M hexane solution, 1.6mL, 1.6mmol) is added into anhydrous CH2Cl2It is in (2mL), solution is cold But to 0 DEG C.By trifluoroacetic acid (0.12mL, 1.6mmol) CH2Cl2(2mL) solution is added dropwise in the diethyl zinc solution, will be obtained The mixture obtained stirs 20 minutes in 0 DEG C.Then the CH of diiodomethane (0.13mL, 1.6mmol) is added2Cl2(2mL) solution, will Reactant is stirred for 20 minutes in 0 DEG C.Then by 5- (1- (bis- fluoro- 4- of 2,5- (((3S, 6R) -3- methyl isophthalic acids, 1- titanium dioxides -6- Phenyl -1,2- thiazan -2- bases) methyl) phenyl) -3- hydroxyls -3- (propyl- 1- alkene -2- bases) cyclobutyl) oxazoles -2 (3H) -one (174mg, 0.32mmol) is dissolved in CH2Cl2(2mL), adds to CF3CO2ZnCH2In I solution.The solution of acquisition is stirred at room temperature 30 Minute, then it is quenched using the aqueous ammonium chloride solution (25mL) of saturation, uses CH2Cl2(3 × 10mL) is extracted, dried over magnesium sulfate, Concentration, is purified by chiral supercritical fluid chromatography, is obtained target compound, is single diastereoisomer (26.3mg).
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),7.50–7.43(m,2H),7.43–7.30(m,3H), 7.25-7.09 (m, 2H), 6.63 (s, 1H), 4.62-4.45 (m, 2H), 4.36 (d, J=17.8Hz, 1H), 4.21-4.03 (m, 1H),2.65–2.57(m,2H),2.46–2.37(m,3H),2.15–2.05(m,1H),1.89–1.72(m,1H),1.72–1.61 (m, 1H), 1.13 (d, J=6.7Hz, 3H), 1.01 (s, 3H), 0.44-0.34 (m, 2H), 0.21-0.13 (m, 2H).LCMS ES+559.2[M+1]+。
Above example compound and the other compounds prepared using same or like method are as shown in table 4, and its is right RORc IC50Value is also as shown in table 4.
Table 4
Table 4
The Proton NMR data of the compound selected in table 4 is as follows, consistent in compound number and table 4.
Compound 15：1H NMR(400MHz,DMSO-d6) δ 9.25 (s, 1H), 8.47 (t, J=5.6Hz, 1H), 7.53- 7.43 (m, 3H), 7.43-7.32 (m, 3H), 7.24 (dd, J=8.2,1.8Hz, 1H), 7.13 (dd, J=12.2,1.9Hz, 1H), 4.57-4.47 (m, 2H), 4.43 (d, J=5.5Hz, 2H), 4.36 (d, J=17.5Hz, 1H), 4.19-4.06 (m, 1H), 3.80-3.70 (m, 2H), 3.52 (t, J=11.2Hz, 2H), 2.80 (s, 3H), 2.47-2.38 (m, 3H), 2.15-2.05 (m, 1H), 1.92-1.74 (m, 3H), 1.71-1.62 (m, 1H), 1.09 (d, J=6.8Hz, 3H).
Compound 16：1H NMR(400MHz,DMSO-d6) δ 8.01 (t, J=5.8Hz, 1H), 7.51-7.43 (m, 3H), 7.43-7.34 (m, 3H), 7.30-7.28 (m, 1H), 7.20 (dd, J=8.1,1.9Hz, 1H), 7.13-7.07 (m, 2H), 4.58-4.46 (m, 2H), 4.36 (d, J=17.5Hz, 1H), 4.19-4.08 (m, 1H), 4.06 (d, J=5.7Hz, 2H), 3.79–3.66(m,5H),3.48–3.37(m,2H),2.47–2.37(m,3H),2.15–2.04(m,1H),1.89–1.74(m, 3H), 1.72-1.62 (m, 1H), 1.09 (d, J=6.9Hz, 3H).
Compound 17：1H NMR(500MHz,DMSO-d6) δ 12.55 (s, 1H), 8.07 (t, J=5.8Hz, 1H), 7.50- 7.44 (m, 3H), 7.44-7.18 (m, 6H), 7.10 (dd, J=12.3,1.8Hz, 1H), 4.58-4.47 (m, 2H), 4.36 (d, J =17.5Hz, 1H), 4.18-4.06 (m, 3H), 3.77-3.69 (m, 2H), 3.45-3.36 (m, 2H), 2.48-2.38 (m, 3H), 2.15-2.05 (m, 1H), 1.90-1.74 (m, 3H), 1.71-1.61 (m, 1H), 1.08 (d, J=6.8Hz, 3H).
Compound 33：1H NMR(400MHz,DMSO-d6) δ 7.98 (t, J=5.6Hz, 1H), 7.50-7.44 (m, 2H), 7.44-7.34 (m, 3H), 7.26-7.15 (m, 3H), 5.87 (d, J=1.9Hz, 1H), 4.61-4.47 (m, 2H), 4.37 (d, J =17.9Hz, 1H), 4.34-4.21 (m, 2H), 4.19-4.07 (m, 1H), 3.73-3.54 (m, 7H), 2.48-2.38 (m, 1H), 2.38–2.28(m,2H),2.16–2.06(m,1H),2.01–1.88(m,2H),1.88–1.73(m,1H),1.73–1.63(m, 1H), 1.11 (d, J=6.9Hz, 3H).
Compound 35：1H NMR(400MHz,DMSO-d6) δ 8.04 (d, J=3.0Hz, 1H), 7.48-7.42 (m, 2H), 7.42-7.32 (m, 4H), 7.08 (dd, J=12.2,6.3Hz, 1H), 5.76 (d, J=2.9Hz, 1H), 5.31 (s, 2H), 4.57-4.44 (m, 2H), 4.35 (d, J=17.8Hz, 1H), 4.14-4.01 (m, 1H), 3.82-3.72 (m, 2H), 3.72- 3.58(m,2H),2.70–2.57(m,2H),2.46–2.31(m,1H),2.17–2.02(m,3H),1.87–1.72(m,1H), 1.72-1.60 (m, 1H), 1.09 (d, J=6.9Hz, 3H).
Compound 36：1H NMR(400MHz,DMSO-d6) δ 7.64 (t, J=5.8Hz, 1H), 7.49-7.43 (m, 2H), 7.43–7.34(m,3H),7.25–7.13(m,2H),4.61–4.43(m,4H),4.41–4.31(m,1H),4.22–4.14(m, 2H),4.14–4.06(m,1H),3.74–3.53(m,4H),3.42–3.36(m,1H),3.29–3.21(m,1H),3.04–2.95 (m,1H),2.47–2.37(m,1H),2.35–2.25(m,2H),2.16–2.05(m,1H),1.99–1.87(m,2H),1.86– 1.73 (m, 1H), 1.73-1.61 (m, 1H), 1.11 (d, J=6.9Hz, 3H).
Compound 38：1H NMR(400MHz,DMSO-d6) δ 8.28 (d, J=2.9Hz, 1H), 7.53-7.32 (m, 6H), 7.05 (dd, J=12.1,6.3Hz, 1H), 6.27 (d, J=2.9Hz, 1H), 4.57-4.44 (m, 2H), 4.36 (d, J= 17.6Hz,1H),4.14–4.00(m,1H),3.84–3.62(m,4H),2.63–2.55(m,2H),2.45–2.32(m,1H), 2.30–2.14(m,2H),2.14–2.06(m,1H),1.96(s,3H),1.87–1.74(m,1H),1.71–1.59(m,1H), 1.04 (d, J=6.8Hz, 3H).
Compound 39：1H NMR(400MHz,DMSO-d6) δ 8.43 (d, J=2.8Hz, 1H), 7.61 (d, J=2.1Hz, 1H), 7.50 (dd, J=11.4,6.5Hz, 1H), 7.47-7.42 (m, 2H), 7.42-7.33 (m, 3H), 7.07 (dd, J= 12.1,6.3Hz, 1H), 6.46 (dd, J=3.3,1.1Hz, 1H), 4.57-4.44 (m, 2H), 4.35 (d, J=17.8Hz, 1H), 4.13–4.02(m,1H),3.84–3.75(m,2H),3.75–3.64(m,2H),2.61–2.53(m,2H),2.45–2.37(m, 1H),2.29–2.16(m,2H),2.13–2.05(m,1H),1.86–1.72(m,1H),1.71–1.61(m,1H),1.06(d,J =6.8Hz, 3H).
Compound 59：1H NMR(400MHz,DMSO-d6)δ13.96(1H,s),8.31-8.21(1H,m),7.59(1H,t, ), J=8.0Hz 7.46-7.33 (6H, m), 4.82-4.72 (4H, m), 4.57-4.49 (2H, m), 4.40 (1H, d, J= 17.6Hz),4.28(2H,s),4.16-4.07(1H,m),2.44-2.37(1H,m),2.12-2.05(1H,m),1.88-1.75 (1H,m),1.68-1.61(1H,m),1.11-1.07(3H,m)。
Compound 119：1H NMR(400MHz,DMSO-d6)δ7.49-7.27(7H,m),4.62-4.53(2H,m),4.41 (1H, d, J=17.9Hz), 4.18-4.10 (1H, m), 3.95-3.81 (3H, m), 2.48-2.40 (1H, m), 2.14-2.08 (1H, m), 1.91-1.76 (1H, m), 1.68 (1H, dd, J=2.3,14.2Hz), 1.40 (1H, s), 1.18-1.07 (3H, m).
Compound 120：1H NMR(400MHz,DMSO-d6) δ 7.45-7.29 (6H, m), 7.21 (1H, dd, J=6.2, 11.1Hz), 4.57-4.46 (2H, m), 4.35 (1H, d, J=17.8Hz), 4.13-4.05 (1H, m), 3.05-2.99 (9H, m), 2.74 (2H, dd, J=4.5,12.0Hz), 2.44-2.35 (1H, m), 2.11-2.03 (1H, m), 1.83-1.70 (1H, m), 1.64 (1H, dd, J=2.3,14.2Hz), 1.10 (3H, d, J=6.9Hz).
Compound 123：1H NMR(400MHz,DMSO-d6)δ7.46-7.34(5H,m),7.22-7.14(2H,m),5.30 (1H, d, J=6.9Hz), 4.57-4.47 (2H, m), 4.38-4.23 (2H, m), 4.14-4.04 (1H, m), 3.12-3.03 (2H, M), 2.45-2.32 (3H, m), 2.11-2.05 (1H, m), 1.84-1.71 (1H, m), 1.64 (1H, dd, J=2.3,14.2Hz), 1.12-1.08(3H,m)。
Compound 127：1H NMR(400MHz,DMSO-d6)δ12.23-12.11(1H,m),7.48-7.35(6H,m), 7.27-7.20 (1H, m), 5.22-5.20 (1H, m), 4.61-4.50 (2H, m), 4.38 (1H, d, J=17.6Hz), 4.16- 4.02 (1H, m), 2.90-2.82 (2H, m), 2.70 (2H, dd, J=4.2,12.0Hz), 2.48-2.38 (1H, m), 2.14- 2.06(1H,m),1.85-1.63(2H,m),1.15-1.08(6H,m)。
Compound 128：1H NMR(400MHz,DMSO-d6)δ7.48-7.44(2H,m),7.43-7.35(3H,m),7.29- 7.18(2H,m),5.19-5.18(1H,m),4.61-4.49(2H,m),4.41-4.34(1H,m),4.16-4.10(1H,m), 2.94 (2H, d, J=13.2Hz), 2.66 (2H, d, J=13.2Hz), 2.47-2.37 (1H, m), 2.14-2.06 (1H, m), 1.86-1.73 (1H, m), 1.67 (1H, dd, J=2.4,14.2Hz), 1.27 (3H, s), 1.13 (3H, d, J=7.3Hz).
Compound 132：1H NMR(400MHz,DMSO-d6)δ7.49-7.24(6H,m),7.07-7.04(2H,m),4.61- 4.51 (2H, m), 4.39 (1H, d, J=17.9Hz), 4.18-4.09 (1H, m), 3.56-3.36 (4H, m), 2.48-2.39 (1H, m),2.13-2.07(1H,m),1.85-1.64(2H,m),1.20-1.12(3H,m)。
Compound 139：1H NMR(400MHz,DMSO-d6)δ12.35-12.25(1H,m),7.49-7.33(6H,m), 7.28-7.21 (1H, m), 4.61-4.50 (2H, m), 4.38 (1H, d, J=18.1Hz), 4.16-4.09 (1H, m), 3.18- 3.07(2H,m),3.04-2.90(1H,m),2.46-2.38(1H,m),2.15-2.05(1H,m),1.84-1.73(1H,m), 1.67 (1H, dd, J=1.7,13.9Hz), 1.55-1.52 (1H, m), 1.49-1.46 (1H, m), 1.40 (2H, s), 1.15- 1.08(3H,m)。
Compound 141：1H NMR(400MHz,DMSO-d6)δ12.18-12.13(1H,m),7.48-7.30(6H,m), 7.23 (1H, dd, J=6.2,11.1Hz), 4.96 (1H, s), 4.60-4.49 (2H, m), 4.38 (1H, d, J=17.8Hz), 4.16-4.08(1H,m),2.85-2.77(2H,m),2.67-2.59(2H,m),2.47-2.32(1H,m),2.14-2.06(1H, m),1.86-1.74(1H,m),1.70-1.63(1H,m),1.14-1.11(3H,m),0.89-0.80(1H,m),0.22-0.12 (4H,m)。
Compound 142：1H NMR(400MHz,DMSO-d6)δ7.49-7.19(6H,m),4.96(1H,s),4.61-4.50 (2H, m), 4.38 (1H, d, J=17.9Hz), 4.17-4.00 (1H, m), 2.93 (2H, d, J=13.2Hz), 2.62 (2H, d, J =12.3Hz), 2.14-2.06 (1H, m), 1.85-1.74 (1H, m), 1.66 (1H, dd, J=2.1,14.2Hz), 1.18-1.12 (3H,m),1.11-1.02(1H,m),0.32-0.25(3H,m)。
Compound 145：1H NMR(400MHz,DMSO-d6)δ13.75-13.67(1H,m),8.32-8.30(1H,m), 7.48-7.36 (5H, m), 7.19-7.07 (2H, m), 5.03 (1H, s), 4.58-4.45 (2H, m), 4.33 (1H, d, J= 17.7Hz),4.14-4.00(1H,m),3.07-3.00(2H,m),2.74-2.67(2H,m),2.13-2.05(1H,m),1.84- 1.72 (1H, m), 1.66 (1H, dd, J=2.2,14.3Hz), 1.20-1.04 (6H, m).
Compound 153：1H NMR(400MHz,DMSO-d6)δ12.23-12.23(1H,s),7.51-7.36(6H,m), 7.25 (1H, dd, J=6.2,11.3Hz), 4.61-4.51 (2H, m), 4.40 (1H, d, J=17.8Hz), 4.16-4.08 (1H, M), 2.85-2.81 (2H, m), 2.73 (2H, d, J=6.2Hz), 2.68-2.54 (3H, m), 2.48-2.38 (1H, m), 2.14- 2.07 (1H, m), 1.87-1.75 (1H, m), 1.71-1.64 (1H, m), 1.14 (3H, d, J=6.9Hz)
Compound 167：1H NMR(400MHz,DMSO-d6)H 11.53(1H,s),7.48-7.36(5H,m),7.21- 7.12 (2H, m), 5.07 (1H, s), 4.59-4.46 (2H, m), 4.35 (1H, d, J=17.8Hz), 4.15-4.08 (1H, m), 3.21 (3H, s), 2.92 (2H, d, J=12.5Hz), 2.61-2.54 (2H, m), 2.47-2.31 (1H, m), 2.13-2.06 (1H, M), 1.85-1.62 (2H, m), 1.16 (3H, s), 1.12 (3H, d, J=6.8Hz)
Compound 169：1H NMR(400MHz,DMSO-d6)δ12.21(1H,s),7.48-7.36(5H,m),7.31(1H, Dd, J=6.5,10.3Hz), 7.23 (1H, dd, J=6.2,11.0Hz), 5.29 (1H, s), 4.61-4.49 (2H, m), 4.38 (1H, d, J=17.9Hz), 4.18-4.08 (1H, m), 3.30 (2H, s), 3.28 (3H, s), 3.04 (2H, d, J=13.7Hz), 2.57 (2H, d, J=14.0Hz), 2.47-2.39 (1H, m), 2.13-2.06 (1H, m), 1.85-1.74 (1H, m), 1.67 (1H, Dd, J=2.2,14.3Hz), 1.14 (3H, d, J=6.5Hz)
Compound 170：1H NMR(400MHz,DMSO-d6)δ13.49(1H,s),7.82(1H,br.s),7.49-7.37 (5H, m), 7.15 (1H, dd, J=6.3,11.3Hz), 6.99 (1H, dd, J=6.4,10.9Hz), 5.26 (1H, s), 4.77 (1H, s), 4.60-4.48 (2H, m), 4.37 (1H, d, J=17.7Hz), 4.17-4.11 (2H, m), 2.67-2.63 (2H, m), 2.47–2.28(4H,m),2.22-2.07(2H,m),1.85-1.76(1H,m),1.72-1.65(1H,m),1.31(3H,s), 1.15 (3H, d, J=6.8Hz)
Compound 171：1H NMR(400MHz,DMSO-d6)δ7.48-7.35(6H,m),7.22-7.13(2H,m),4.89 (1H, s), 4.75 (1H, dd, J=6.6,8.8Hz), 4.59-4.47 (2H, m), 4.36 (1H, d, J=17.8Hz), 4.13 (1H, Ddd, J=2.0,6.9,11.8Hz), 3.30-3.25 (1H, m), 3.01 (1H, dd, J=6.9,8.7Hz), 2.57-2.52 (1H, M), 2.48-2.34 (4H, m), 2.14-2.06 (1H, m), 1.87-1.75 (1H, m), 1.67 (1H, dd, J=2.2,14.2Hz), 1.31 (3H, s), 1.12 (3H, d, J=6.8Hz)
The external RORc ligand bindings experiment of embodiment 27
By determining Kiapp、IC50Or suppressing the value of percentage, the experiment is used to determine the efficiency that compound suppresses RORc. The consumptive material used in the embodiment is as shown in Table 5 below.
Table 2
Table 5
It is prepared by filter plate
On the day of experiment, 100 μ L 0.05%CHAPS is added to GFB Unifilter plates (in deionized water) In all holes and soak 1 hour.Prepare 50mM HEPES (pH 7.4), 150mM NaCl and 5mM MgCl2Lavation buffer solution To wash filter plate.In order to prepare experiment buffer solution, BSA is added in lavation buffer solution and reaches 0.01%, added DTT and reach 1mM。
Compound
For IC50Pattern, 10mM compound stock solutions are used into DMSO serial dilutions in DMSO, obtain 20 in DMSO × required final concentration (15uL compound+30uL DMSO).20 × compound stock solution is used to 4 times of buffer solution of experiment in DMSO Be diluted to and reach 5 × final experimental concentration in 25%DMSO (10uL compounds+30uL tests buffer solution).With being set as 50uL The pipette of volume is for several times mixed solution by suction.During for testing, by 5 × compound of the 10uL in 25%DMSO Storing solution is added in breadboard in duplicate.
For 2 points of screenings, 10mM compound stock solutions are diluted to obtain (the 20 times high experiment of 200 μM of concentration in DMSO Concentration), 10 times are then further diluted to reach 20 μM of concentration (20 times of low experimental concentrations).20 × storing solution is buffered with experiment To reach 5 × experimental concentration (50uM and 5uM), 10uL is added to for liquid (10uL compounds+30uL tests buffer solution) 4 times of dilution In two breadboards, for duplicate.Each concentration is tested on 2 plates, every group of 80 compounds use 4 breadboards (1 μM and 10 μM, n=2).
Non-specific binding (NSB) sample, total binding (TB) sample and without acceptor (No R) sample
For above-claimed cpd, the 25-HYDROXY CHOLESTEROL (1uM) for determining NSB signal levels is prepared in DMSO, so Diluted afterwards in buffer solution is tested to obtain 5uM ultimate density.For the 25- in testing buffer solution in 25%DMSO/75% Hydroxy cholesterol；It is used for NSB samples per hole 10uL.For total binding and 10uL's contained in the hole without acceptor sample measure per hole 25%DMSO/75% tests buffer solution.
Radioligand 25- [3H] hydroxy cholesterol) preparation
By 25- [3H] hydroxy cholesterol dilutes in buffer solution is tested, obtain 15nM, vortex mixed.To all Kong Zhongjia Enter 20uL and reach in test 6nM ultimate densities.
It is prepared by acceptor
It was found that the optium concentration of RORc acceptors is 0.6ug/mL.Receptor reserve liquid is diluted in determination test buffer solution, is obtained Obtain the 1.5ug/mL in buffer solution is tested.20 μ L are added into all holes.For No R samples, buffer solution generation is tested with 20 μ L For receptor solution.
Sample is added on to plate and is cultivated
Breadboard is 96 hole polypropylene V bottom plates.By 5 × chemical combination of the 10uL in testing buffer solution in 25%DMSO/75% Thing is added in instrument connection.10uL 25%DMSO/75% experiment buffer solutions are added to total binding or without in receptor hole.Will be 5 μM of 25-HYDROXY CHOLESTEROLs of 10uL in 25%DMSO/75% experiment buffer solutions are added in NSB holes.It will be buffered in experiment The 20uL prepared in liquid 15nM 25- [3H] hydroxy cholesterol is added in all holes.By 20uL 1.5ug/mL RORc by In body adding hole (or 40uL experiment buffer solutions are added in No R holes).Add to hole, plate is incubated 3 hours in 25 DEG C.
Filtering
Using Packard Filtermate collectors, after incubated samples transfer, filter plate is washed 4 times.Plate is completely dry Dry filtering (at 50 DEG C 2 hours or overnight at room temperature).50uL Microscint 0 are added in all holes, Reading on Topcount Protocol Inverted.
Final concentration
Final concentration is as follows：50mM HEPES buffer solutions (pH 7.4)；150mM NaCl；1mM DTT；5mM MgCl2； 0.01%BSA；5%DMSO；0.6ug/mL RORc acceptors；6nM 25-[3H] hydroxy cholesterol.For NSB holes, equally exist 1uM 25-HYDROXY CHOLESTEROLs.
Embodiment 28：RORc co-activation factor peptide binding tests
Experiment is in black 384Plus F Proxiplates (Perkin-Elmer 6008269) with 16mL reaction volumes Carry out.Except experiment is matched somebody with somebody in vitro, by all experiment compositions in the auxiliary adjustment factor buffer solution D containing 5mM DTT Mix in (Invitrogen PV4420), be added to the concentration of twice of its final concentration in 8mL volumes in plate.Then by 2 × end The experiment part of concentration is added in the common regulatory factor buffer solution D of the 8 μ l containing 5mM DTT and 4%DMSO hole.Final temperature Educate comprising 1 × altogether regulatory factor buffer solution D, 5mM DTT, experiment part, 2%DMSO, 50nM biotinyl- CPSSHSSLTERKHKILHRLLQEGSPS(American Peptide Company；Vista,CA)、2nM Europium Anti-GST (Cisbio 61GSTKLB), 12.5nM Streptavidins-D2 (Cisbio 610SADAB), 50mM KF and 10nM Bacterial expression comprising N- ends 6xHis-GST- mark and Accession NP_005051 residue 262-507 people RORc ligand binding domain albumen.Duplicate 10 experiment ligand concentrations of test.By reaction plate under room temperature (22-23 DEG C) black Incubate 3 hours in the dark after, according to europium/D2HTRF schemes (ex 320, em in EnVision plate reader (PerkinElmer) 615 and 665,100s time delay, 100 flickers, 500 μ s windows) read plate.Time resolution FRET signals at 665nm divided by Signal at 615nm is to produce the signal ratio in each hole.By the signal ratio in the hole containing RORc and peptide but without experiment part Rate mean deviation is set as 0% effect, and the signal ratio of the blank well containing co-activation factor peptide but no RORc is averaged simultaneously It is set as -100% effect.Basic (composing type) signal is presented in RORc in this experiment, and experiment part can increase or decrease relatively In the horizontal signal ratio of the basis signal.RORc activators can increase signal ratio in this experiment, produce positive % effects Fruit value.Inverse agonist can reduce signal ratio, produce negative % Effect values.EC50Value is can to provide half maximum efficiency (to increase Add deduct few stimulus) test compound concentration, it can pass through Genedatasoftware (Genedata；Basel, Switzerland) calculated using following equations：
%Effect=S0+{(Sinf–S0)/[1+(10logEC 50/10c)n]}
Wherein S0Activity level when for test compound concentration being zero, SinfFor test compound concentration infinity when Activity level, EC50Reach concentration during maximum efficiency 50% for activity, c is log unit concentration, bent corresponding to dosage-response The x-axis of line chart, n are hill coefficient (in EC50Locate slope of a curve).
Embodiment 29：Arthritis mouse model
By male DBA/1 (DBA/1OlaHsd, Harlan Laboratories) Mouse feeder of 8-10 week old in Wu Te Determine in pathogen (SPF) animal facility.By the way that collagen-induced arthritis is subcutaneously injected twice in tail bottom.Initial injection the (the 0th My god) using being emulsified in isometric CFA containing 4mg/ml mycobacterium tuberculosis (M.tuberculosis) (Chondrex) II type bovine collagens albumen (2mg/ml, from Chondrex, Redmond, Wash.).29th day, CII booster shots liquid is existed Emulsified in incomplete Freund's adjuvant (IFA).Every animal passes through subcutaneous/intracutaneous note in the afterbody apart from 2-3 centimetres of mouse body Penetrate and receive 0.1mL emulsions.Booster shots position is different from initial injection near sites, closer to the body of animal. OR-1050 is prepared in HRC-6 as described above.On weekdays, animal receives the HRC-6 or mouth of two dosage (a.m. and p.m.) Take 50mg/kg OR-1050 (2.5mls/kg).At weekend, the 100mg/kg (5mls/kg) of single dose is given.
According to the CIA clinical symptoms of following qualitative grade, daily observation mouse.Every claw all by individual inspiration and is beaten Point.0 grade, normally；1 grade, slight but clear and definite ankle-joint or wrist joint are red and swollen, or be limited to the obvious rubescent of single finger and Swelling, no matter impacted finger is several；2 grades, ankle or wrist are red and swollen；3 grades, whole claw includes the severe redness of finger And swelling；4 grades, include the most serious inflammation redness of multi-joint limbs.In order to judge the accumulation of the disease severity of every animal Degree, by amounting to the summation of daily rear solid end measured value between the 24th day and the 48th day, below the curve for calculating every animal Product.
Embodiment 30：Muscular sclerosis disease mouse model I
Heavy 17-20 grams of 4-6 week old female mices for belonging to C57BL/6 kinds are tested.Using 95% purity Synthesis myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) (Invitrogen) active inducing experimental itself Allergic encephalomyelitis (EAE).By every mouse anesthesia and 200 μ g of receiving MOG35-55Peptide and 15 μ from Quilija barks G saponin extracts, it is emulsified in 100 μ L phosphate buffered saline (PBS)s.25uL dimensions subcutaneous is expelled to four sides abdomen part Domain.The 200ng pertussis toxins in 200 μ L PBS are also injected intraperitoneally in mouse.Second of identical pertussis is injected after 48 hours Toxin.
The compounds of this invention is administered with the dosage selected.Control-animal receives 25 μ L DMSO.Daily treatment is after being immunized Extend within 26th day the 36th day.Clinical score was carried out daily from immune latter 0th day to the 60th day.Using following scheme to clinical body Sign is scored：0, without detectable presentation；0.5, distal end tail is weak, cuddles up in a heap and behavior is quiet；1, it is completely weak Tail；1.5, weak tail and hind limb weakness (instability of gait, hind leg earth-grasping force are poor)；2, unilateral partial hind paralysis； 2.5, bilateral hind limb paralysis；3, bilateral hind leg is paralysed completely；3.5, hind leg paralysis and unilateral fore-limb paralysis completely；4, hind leg is with before Limb is paralysed (Eugster etc., Eur J Immunol 2001,31,2302-2312) completely.
Inflammation and demyelinate can be assessed by the institutional framework of the CNS sections to EAE mouse.Put to death after 30 or 60 days small Mouse, take out whole spinal cord and be placed in 4 DEG C of 0.32M sucrose solutions overnight.Prepare tissue and cut into slices.Using the solid blue dyes of Lu Kesuo Color observes the region of demyelinate.Inflammation is highlighted by the core of deep colour dyeing monocyte using haematine and eosin dyeing Region.Blind counts the immunocyte dyed with H＆E under an optical microscope.Section is divided into the material of grey and white, often Individual section all manually counts, and is then combined with obtaining the complete information of section.It is thin with AntiCD3 McAb+monoclonal antibody immunity mark T Born of the same parents.After washing, section is incubated together with goat anti-rat HRP secondary antibodies.Then section is washed and uses methyl green counterstain. Lysis buffer processing is used to separate red blood cell from the splenocyte of immune latter 30 and 60 days mouse separation.Then by cell again It is suspended in PBS and counts.With about 3 × 106Individual cell/mL density incubated cell together with 20ug/mL MOG peptides Night.Use the IFN-γ protein in appropriate supernatant of the mouse IFN-γ immunoassay system analysis from stimulated cell It is horizontal.
Embodiment 31：Muscular sclerosis disease mouse model II
In the model, by female rodent isoflurane anesthesia, at the 0th day of this research, two at back Individual injection location contains 1mg/mL neurons antigen (such as myelin alkaline protein, myelin oligodendroglia glycoprotein, albumen Lipid protein) and 4mg/mL mycobacterium tuberculosis incomplete Freund's adjuvant.Then terminated since the 0th day until studying, often It by subcutaneous, intraperitoneal or it is oral in a manner of give the target compound of effective dose.Daily observation degree of paralysis is as efficiency Linear module.
Embodiment 32：Psoriasis mouse model I
Serious merging immune deficiency (SCID) mouse model can be used for the efficiency for assessing compounds for treating people's psoriasis (Boehncke, Ernst Schering Res Found Workshop 2005,50,213-34；With Bhagavathula etc., J Pharmacol Expt'l Therapeutics 2008,324 (3), 938-947).In short, SCID mice is used as group Knit recipient.To the back table that Recipient mice is transplanted in each normal or psoriasis volunteer (people) biopsy Face.1 to 2 week started to treat after transplanting.Animal with application on human skin graft is divided into multiple treatment groups.Animal treatment two daily It is secondary, totally 14 days.When treatment end, animal is taken pictures, is then euthanized.By people's tissue of transplanting and the mouse skin of surrounding Operation is taken out and fixed in 10% formalin, and sample is used for into microexamination.Measure epidermal thickness.Histotomy is adopted Dyed with Proliferation marker Ki-67 antibody and with anti-human CD3.sup.+ monoclonal antibodies to detect the people T in transplanting tissue Lymphocyte.Section can also be detected using the antibody of anti-c-myc and beta-catenin.Positive response to treatment is reflected in silver In the reduction for considering disease skin graft mean epidermal thickness to be worth doing.Positive response also reduces with the expression of Ki-67 in keratinocyte to be had Close.
Embodiment 33：Psoriasis mouse model II
Using imiquimod model (Imidquimod model) (Fits etc., Journal of of scytitis Immunology,2009,182：5836-5845), by BALB/c, Il17c+ of 10-12 week old /+or Il17c-/- or Il17re+ /+or Il17re-/- mouse shave light back and auris dextra using 50mg Aldara cremes, (5% miaow quinoline is not daily Spy, Graceway, 3M), continue 5 days.Clinical score and ear thickness measure are carried out daily.Score the table based on psoriasis symptom It is existing, such as erythema, the scales of skin that peel off and thickness：0, without disease.1, very slight erythema, thicken and the scales of skin that peel off, relate to very slight And area is small.2, slight erythema companion slightly thickens and the scales of skin that peel off, and it is small to be related to area.3, moderate erythema is thickened with the scales of skin that peel off (no with moderate Regular patch shape), be related to area it is small (<25%).4, Severe erythema with it is obvious thicken with the scales of skin that peel off (irregular and patch shape), It is related to moderate area (25-50%).5, Severe erythema with it is obvious thicken with the scales of skin that peel off (irregular and patch shape), be related to area Greatly (>50%).Ear was collected at the 5th day and back organizes to be used for Histological assessment.In imiquimod (IMQ) mouse of psoriasis In model the effect of comparative compound.As described above, Balb/c mouse (10 male/groups) are every on the back and auris dextra for shave light It receives local I MQ (5% emulsifiable paste), totally 5 days.From the -5th day to the+5th day, animal received the representative compound of oral dose Or DMF (45 or 90mg-eq MMF/kg, twice daily) or carrier.Scores of erythema is main evaluation index.In male Balb/C The compound scores of erythema value of 10 days tested in mouse with 90mg-eq MMF/kg BID oral doses is listed in the table below in 3.Number According to display, compound and the DMF of the disclosure are equivalent.
Embodiment 34：IBS mouse model I
The effect for the treatment of of inflammatory bowel can be evaluated according to following documents methods described：Jurjus etc., J Pharmaocol Toxicol Methods 2004,50,81-92；Villegas etc., Int'l Immunopharmacol 2003,3,1731- 1741；With Murakami etc., Biochemical Pharmacol 2003,66,1253-1261.It is in short, female ICR is small Mouse is divided into multiple treatment groups, wherein giving water (control), the 5%DSS in running water is given when testing and starting to induce colon Inflammation, or give the test compound of various concentrations.After test compound is given 1 week, also by the DSS in 5% running water Give reception test compound the group of 1 week.At the end of experiment, all mouse are put to death, take out large intestine.Obtain mucous membrane of colon Sample simultaneously homogenizes.Quantitative determine pro-inflammatory mediator (such as IL-1 α, IL-1 β, TNF α, PGE 2 and PGF2 α) and protein compression Degree.Histological examination is carried out to the large intestine of each excision, and to the injury severity score of colon.
Embodiment 35：Chronic obstructive pulmonary disease mouse model
Martorana etc., Am J Respir Crit Care Med 2005,172,848-835；With Cavarra etc., Am J Respir Crit Care Med 2001,164,886-890 smoke from cigarette model can be used for assessing treatment pulmonary emphysema Efficiency.In brief, by 6 week old C57B1/6J male mices 20 points in room air or the smog of five cigarette Clock.For acute study, mouse is divided into three groups, every group of 40 animals.Then it is 10 small these groups to be divided into following every group Four subgroups of mouse：(1)/air exposure is not treated；(2)/smog exposure is not treated；(3) administration adds test compound for the first time Upper smog exposure；(4) second of administration of test compound.In the first set, at the end of BAL fluid exposes Assess TAC (trolox equivalent antioxidant capacity).In the second set, use is commercially available Cell factor and chemotactic factor (CF) of the cell factor plate in 4 hours measure in BAL fluid；3rd group at 24 hours Bronchoalveolar Lavage Fluid Cells are assessed to count.
In chronic research, by mouse in the smog of room air or daily three cigarettes, 5 days/week, continue 7 Month.Use five groups of animals：(1)/air exposure is not treated；(2) administration adds air exposure to test compound for the first time；(3) do not control Treatment/smog exposure；(4) second of administration smoke adding mist exposure of test compound；(5) administration adds above-mentioned test compound for the first time Smog exposes.Room air or smoke from cigarette are chronicly exposed to after seven months, every group of 5-12 animal is put to death, uses formalin Tracheal strips fix lung.Pulmonary volume passes through draining measurement.Carry out lung dyeing.The assessment of pulmonary emphysema includes average linear intercept and interior Surface area.The bulk density of macrophage is marked using anti-mouse Mac-3 monoclonal antibodies with immunohistochemical method, is passed through a little Count and determine.When at least one or more medium-sized bronchus/lung shows periodic acid-Schiff (Schiff) for determining desmosine During stained positive, it is believed that mouse has goblet cell metaplasia, by fresh lung homogenate, processing, passes through efficient liquid phase chromatographic analysis.
Embodiment 36：Asthma mouse model
A Single Intake by Inhalation allergen challenge can induce some personal and animal model acute increases of airway reactivity.So And anaphylactogen suction repeatedly has shown more significant, consistent and lasting airway reactivity increase.It is long-term to repeat to suck The mouse model of anaphylactogen has been used for the long-term effect of study of lung anaphylactia, and depicts with causing air flue in mankind's lung High response related cell, mechanism, molecule and medium.
Crystallization OVA is obtained from Pierce Chem.Co. (Rockford, Ill.), and alum (alum) is obtained from Sigma Chem.Co. (St.Louis, Mo.), apyrogeneity distilled water are obtained from Baxter, Healthcis Corporation (Deerfield, Ill.), 0.9% sodium chloride (physiological saline) are obtained from Lymphomed (Deerfield, Ill.), Trappsol.TM.HPB-L100 (the hydroxypropylβ-cyclodextrin aqueous solution；The 45wt/vol% aqueous solution) it is obtained from Cyclodextrin Technologies Development,Inc.(Gainesville,Fla.).By OVA (500ug/ml physiological saline) and wait body 10% long-pending (wt/vol) alum mixes in distilled water.After incubating 60 minutes at room temperature, mixture (is used into 10N NaOH Adjust to pH 6.5) centrifuged 5 minutes with 750g；Sediment is resuspended in the distilled water of initial volume, in one hour Use.By selective 5- lipoxidase inhibitors Zileuton (Zileuton) (N- [1- benzos [b] thiophene -2- bases ethyl]-N- hydroxyls Base urea；J.Pharmacol Exp Ther.1991；256：929-937) it is dissolved in Trappsol.TM.Histatek, Inc. (Seattle, Wash.) is to provide mast cell degranulation inhibitor, f-Met-Leu-Phe-Phe (" HK-X ").
According to various criterion scheme, female BAl BIc/c mouse (6-8 week old) receives i.p. injection 0.2mL's (100ug) OVA and alum (J.Exp.Med.1996；184:1483-1494).Mouse is used in 0.2ml intraperitoneal injection physiological saline Ketamine (0.44mg/ml)/xylazine (6.3mg/ml) anesthesia, then gives through intranasal (i.n.) respectively on the different dates The OVA of the 100 μ g in the 0.05ml physiological saline and 50ug OVA in 0.05mL physiological saline through intranasally.Using Two control groups：First group of intraperitoneal injection contains the physiological saline of alum and the physiological saline without alum；Second group of abdomen OVA of the chamber injection containing alum, not aluminated OVA and single physiological saline.
Obtain tracheae and left lung (right lung can be used for bronchoalveolar lavage (" BAL ") as described below) and at room temperature Solidify in 10% neutral formalin solution about 15 hours.After being embedded in paraffin, the tissue is cut into 5 μm of sections, using not Same dyeing or immune labeled further processing.Dyed using Discombe eosinophil for counting methylenum careuleum counterstain Cell quantity.Per unit air flue area (2,200um2) eosinophil number determined by morphometry (J.Pathol.1992；166：395-404；Am Rev Respir Dis.1993；147：448-456).With the colors of Masson tri- Decoration method identifies fibrosis.Air way mucus is identified by following colouring method：Methylenum careuleum, haematine and eosin, mucoprotein kermes Red, alcian blue and A Erxin indigo plants/periodic acid-Schiff (PAS) reaction (Troyer, H., " Carbohydrates " in Principles and Techniques of Histochemistry (" the carbon hydrates in histochemistry's principle and technology Thing "), Little, Brown and Company, Boston, Mass., 1980:89-121；Sheehan, D.C. etc., " Carbohydrates " in Theory and Practice of Histotechnology (histotechnology theory and practice In " carbohydrate "), Battle Press, Columbus, Ohio, 1980:159-179).Mucoprotein uses mucoprotein Cochineal solution dyes；Using tropeolin G counterstain.Acid mucoprotein and sulphation mucilaginous substance are contaminated with the alcian blue that pH is 2.5 Color；Use core fast red counterstain.Neutral and acidic mucus matter is reacted by alcian blue and PAS that pH is 2.5 to be differentiated.Air flue sticks Liquid chocking-up degree (diameter 0.5-0.8mM) can also be assessed by morphometry.Percent blockage of the mucus to airway diameter It is classified as the sxemiquantitative rank from 0 to 4+.Histology and morphological analysis can be by the uncomprehending individuals of conceptual design Carry out.
At the 28th day, after last time physiological saline or OVA intraperitoneal injections (i.n.) are administered 24 hours, by foregoing Mechanics of lung (10,1958 of the plethysmography method in mouse in vivoassay methacholine venous transfusion；192:364-368； J.Appl.Physiol.1988；64:2318-2323；J.Exp.Med.1996；184:1483-1494).
After left lung mainstem bronchus ligation, right lung can use 0.4ml physiological saline lavation 3 times.Using hemacytometer meter Number is derived from BAL fluid (BAL) liquid cell in the sample that 0.05ml equal portions are collected, and remaining liquid is at 4 DEG C Centrifuged 10 minutes with 200g.Supernatant can be stored in 70 DEG C until carrying out class dodecylic acid analysis.By cell pellet containing Have after being suspended again in 10% bovine serum albumin(BSA) (" BSA ") physiological saline, BAL cell smears are prepared on slide.For Dyeing eosinophil, by dry slide Discombe dilution (0.05% eosin in distilled water With 5% acetone (vol/vol)；J.Exp.Med.1970；131：5-8 minutes 1271-1287) are dyed, 0.5 point is rinsed with water Clock, redyed 2 minutes using 0.07% methylenum careuleum.
Although describing the present invention by reference to the particular of the present invention, those skilled in the art should manage Solution, in the case of without departing substantially from true spirit and scope of the present invention, can carry out various changes and can equally be replaced Change.Furthermore, it is possible to carrying out a variety of modifications to particular situation, material, combination of materials, method, processing step adapts it to this hair Bright objective mind and scope.All such modifications should be included in the range of claim.

Claims (24)

1. compound of formula I or its pharmaceutically useful salt：
Wherein：
M is 0 or 1；
N is 0 or 1；
P is 0-3；
Q is 0,1 or 2；
R is f1,2 or 3；
A is：
Key；
-(CRjRk)t-；
-C(O)-(CRjRk)t-；
-(CRjRk)t-C(O)-；
-NRa-(CRjRk)t-；
-(CRjRk)t-NRa-；
-C(O)NRa-(CRjRk)t-；
-(CRjRk)t-NRaC(O)-；
-O-(CRjRk)t-；
-(CRjRk)t-O-；
-S-(CRjRk)t-；
-(CRjRk)t-S-；
-SO2-(CRjRk)t-；
-(CRjRk)t-SO2-；Or
T is 0-4；
W is：
-CRbRc-；
-O-；
-S-；
-SO2-；Or
-NRd-；
X1、X2、X3And X4One of be N, remaining is CRe；
Or X1、X2、X3And X4In two be N, remaining is CRe；
Or X1、X2、X3And X4In three be N, another is CRe；
Or each X1、X2、X3And X4For CRe；
Y is：
-O-；
-S-；
-SO2-；
-CRfRg-；Or
-NRh-；
Z is：
Key；
-C1-6Alkylidene-；
-NRp-C1-6Alkylidene；
-C1-6Alkylidene-NRp-；
-NRp-；
-C(O)-；
-C(O)NRp-；
-C(O)NRp-C1-6Alkylidene；
-NRpC(O)-；
-NRpC(O)-C1-6Alkylidene；
-C1-6Alkylidene-O-；
-O-C1-6Alkylidene-；Or
-C1-6Alkylidene-O-C1-6Alkylidene-；
Het is：
Heteroaryl, it is selected from：
Oxazolyl；
Isoxazolyl；
Thiazolyl；
Isothiazolyl；
Pyrazolyl；
Triazolyl；
Oxadiazolyl；
Thiadiazolyl group；
Pyridine radicals；
Pyrimidine radicals；
Pyrazinyl；Or
Imidazole radicals；
Wherein each heteroaryl can be unsubstituted or by RmSubstitution is one or more times；Or
Heterocyclic radical, it is selected from：
Oxetanylmethoxy；
Tetrahydrofuran base；
THP trtrahydropyranyl；
Pyrrolidinyl；
Piperidyl；
Piperazinyl；
Oxazole alkyl；
Imidazolidinyl；
Morpholinyl；
Thio-morpholinyl；Or
1,1- dioxothiomorpholinyls；
Wherein each heterocyclic radical can be unsubstituted or by RnSubstitution is one or more times；
R1、R2、R3、R4、R5、R6、R7And R8Each stand alone as：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Or R3And R4Ethylidene is formed together with the atom connected with them；
Or R3And R43,4,5,6 or 7 yuan of saturations or fractional saturation ring can be formed together with the atom connected with them, its Optionally-O- ,-NR can be selected from comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R5And R63,4,5,6 or 7 yuan of saturations or fractional saturation ring can be formed together with the atom connected with them, its Optionally-O- ,-NR can be selected from comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R7And R83,4,5,6 or 7 yuan of saturations or fractional saturation ring can be formed together with the atom connected with them, its Optionally-O- ,-NR can be selected from comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R3And R4One of and R5And R6One of and their atoms for being connected can form 3,4,5,6 or 7 yuan of saturations together Or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by Ri Substitution is one or more times；
Or R5And R6One of and R7And R8One of and their atoms for being connected can form 3,4,5,6 or 7 yuan of saturations together Or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by Ri Substitution is one or more times；
Each R9Stand alone as：
C1-6Alkyl；
Halogen；
C1-6Alkoxy；Or
Cyano group；
Wherein described C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；
R10For：
Hydrogen；
Carboxyl；
C1-6Alkyl-carbonyl；
C1-6Alkoxy-carbonyl；
Oxo；
Hydroxyl；
Amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Cyano group；
Hydroxyl-C1-6Alkyl；
N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl；
N- hydroxyls-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-amino carbonyl；
Halogen；Or
C1-6Alkyl, it can be unsubstituted or be substituted one or more times by halogen or oxo；
R11For：
Hydrogen；
Halogen；
Carboxyl；
C1-6Alkyl-carbonyl；
C1-6Alkoxy-carbonyl；
Oxo；
Hydroxyl；
Amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
C1-6Alkyl-sulfonylamino；
C1-6Alkyl-sulfonylamino-C1-6Alkyl；
Cyano group；
Hydroxyl-C1-6Alkyl；
N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl；
N- hydroxyls-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-amino carbonyl；Or
C1-6Alkyl, it can be unsubstituted or be substituted one or more times by halogen or oxo；
Or R10And R113,4,5,6 or 7 yuan of saturations or fractional saturation ring can be formed together with the atom connected with them, its Optionally-O- ,-NR can be selected from comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or R10And R11Double bond is formed together with the atom connected with them；
R12For：
Hydrogen；
Halogen；
Carboxyl；
C1-6Alkyl-carbonyl；
C1-6Alkoxy-carbonyl；
Oxo；
Hydroxyl；
Amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Cyano group；
Hydroxyl-C1-6Alkyl；
N-C1-6Alkoxy -C1-6Alkyl-aminocarbonyl；
N- hydroxyls-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-amino carbonyl；Or
C1-6Alkyl, it can be unsubstituted or be substituted one or more times by halogen or oxo；
R13For：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Ra、Rb、RcAnd RdEach stand alone as：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Or RbAnd Rc3,4,5,6 or 7 yuan of saturations or fractional saturation ring can be formed together with the atom connected with them, It optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
Or RbAnd RcOne of and R7And R8One of and their atoms for being connected can form 3,4,5,6 or 7 yuan of saturations together Or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by Ri Substitution is one or more times；
Or RbAnd RcOne of and R5And R6One of and their atoms for being connected can form 3,4,5,6 or 7 yuan of saturations together Or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by Ri Substitution is one or more times；
Each ReStand alone as：
Hydrogen；
C1-6Alkyl；
Halogen；
C1-6Alkoxy；Or
Cyano group；
Wherein described C1-6Moieties can be unsubstituted or by halogen, hydroxyl or C1-6Alkoxy substitutes one or more times；
RfFor：
Hydrogen；
Halogen；
C1-6Alkoxy；Or
C1-6Alkyl, it can be unsubstituted or by halogen, hydroxyl or C1-6Alkoxy substitutes one or more times；
RgFor：
Hydrogen；
C1-6Alkyl；
C3-6Cycloalkyl, it can be unsubstituted or by C1-6Alkyl substitution is once or secondary；
C2-6Alkenyl；
C3-6Cycloalkenyl group；
C3-6Cycloalkyl-C1-6Alkyl；
Halogen；
C1-6Alkyl-carbonyl；
C3-6Cycloalkyl-carbonyl；
C3-6Cycloalkyl-C1-6Alkyl-carbonyl；
Cyano group-C1-6Alkyl-carbonyl；
Hydroxyl-C1-6Alkyl-carbonyl；
C1-6Alkoxy -C1-6Alkyl-carbonyl；
Carboxyl；
N- cyano group-amino carbonyl；
N- cyano group-N-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkyl-ethanamidine base；
N, N '-two-C1-6Alkyl-ethanamidine base；
N '-cyano group-N-C1-6Alkyl-ethanamidine base；
N'- hydroxy-acetamidine bases；
N'-C1-6Alkoxy-ethanamidine base；
N'- hydroxy-ns-C1-6Alkyl-ethanamidine base；
N'-C1-6Alkoxy-N-C1-6Alkyl-ethanamidine base；
2- nitros -1-N-C1-6Alkyl amino-vinyl；Formoxyl；
C1-6Alkyl-sulfonyl base；
C3-6Cycloalkyl-sulfonyl；
C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；
C1-6Alkyl-sulfonyl base-C1-6Alkyl；
Amino carbonyl；
Carbonylamino；
N- hydroxy-amino carbonyls；
N-C1-6Alkoxy-amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
Amino carbonyl-C1-6Alkyl；
N-C1-6Alkyl-aminocarbonyl-C1-6Alkyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl-C1-6Alkyl；
C1-6Alkoxy-carbonyl；
N- hydroxy-ns-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Amino-sulfonyl；
N-C1-6Alkyl-amino sulfonyl；
- the C of N, N- bis-1-6Alkyl-amino sulfonyl；
Cyano group；
C1-6Alkoxy；
C1-6Alkyl-sulfonylamino；
N-C1-6Alkyl-sulfonylamino carbonyl；
N-(C1-6Alkyl-sulfonyl base)-N-C1-6Alkyl-aminocarbonyl；
N-(C1-6Alkyl-sulfonyl base)-amino-C1-6Alkyl；Amino；
N-C1-6Alkyl-amino；
- the C of N, N- bis-1-6Alkyl-amino；
Halo-C1-6Alkyl；
Phenyl；
Heterocyclic radical；
Heteroaryl；
C1-6Alkyl-carbonylamino；
Carbonylamino；Or
Hydroxyl；
Wherein described C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；And
Wherein described phenyl, heterocyclic radical, heteroaryl, C3-6Cycloalkyl, C3-6Cycloalkenyl group and C3-6Cycloalkyl-C1-6Moieties can be with It is unsubstituted or by RiSubstitution is one or more times；
Or RfAnd RgOxo can be formed together；
Or RfAnd Rg4,5,6 or 7 yuan of saturations or fractional saturation ring can be formed together with the atom connected with them, it can To be optionally selected from-O- ,-NR comprising 1 or 2a- or-S- hetero atom, it can be optionally by RiSubstitution is one or more times；
RhFor：
Hydrogen；
C1-6Alkyl；
C3-6Cycloalkyl；
C3-6Cycloalkenyl group；
C3-6Cycloalkyl-C1-6Alkyl；
C1-6Alkyl-carbonyl；
C3-6Cycloalkyl-carbonyl；
C3-6Cycloalkyl-C1-6Alkyl-carbonyl；
Cyano group-C1-6Alkyl-carbonyl；
Hydroxyl-C1-6Alkyl-carbonyl；
C1-6Alkoxy -C1-6Alkyl-carbonyl；
N- cyano group-amino carbonyl；
N- cyano group-N-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkyl-ethanamidine base；
N, N '-two-C1-6Alkyl-ethanamidine base；
N '-cyano group-N-C1-6Alkyl-ethanamidine base；
N'- hydroxy-acetamidine bases；
N'-C1-6Alkoxy-ethanamidine base；
N'- hydroxy-ns-C1-6Alkyl-ethanamidine base；
N'-C1-6Alkoxy-N-C1-6Alkyl-ethanamidine base；
2- nitros -1-N-C1-6Alkyl amino-vinyl；
Formoxyl；
C1-6Alkyl-sulfonyl base；
C3-6Cycloalkyl-sulfonyl；
C3-6Cycloalkyl-C1-6Alkyl-sulfonyl base；
C1-6Alkyl-sulfonyl base-C1-6Alkyl；
Amino carbonyl；
N- hydroxy-amino carbonyls；
N-C1-6Alkoxy-amino carbonyl；
N-C1-6Alkyl-aminocarbonyl；
N- hydroxy-ns-C1-6Alkyl-aminocarbonyl；
N-C1-6Alkoxy-N-C1-6Alkyl-aminocarbonyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl；
Amino-sulfonyl；
N-C1-6Alkyl-amino sulfonyl；
- the C of N, N- bis-1-6Alkyl-amino sulfonyl；
Cyano group；
C1-6Alkyl-sulfonylamino；
C1-6Alkyl-sulfonylamino-C1-6Alkyl；
N-(C1-6Alkyl-sulfonyl base) amino carbonyl；
N-(C1-6Alkyl-sulfonyl base)-N-C1-6Alkyl-aminocarbonyl；
N-(C1-6Alkyl-sulfonyl base)-amino-C1-6Alkyl；
Amino carbonyl-C1-6Alkyl；
N-C1-6Alkyl-aminocarbonyl-C1-6Alkyl；
- the C of N, N- bis-1-6Alkyl-aminocarbonyl-C1-6Alkyl；
C1-6Alkoxy-carbonyl；
Phenyl；
Heterocyclic radical；Or
Heteroaryl；
Wherein described C1-6Moieties can be unsubstituted or be optionally substituted by halogen one or more times；And
Wherein described phenyl, heterocyclic radical, heteroaryl, C3-6Cycloalkyl, C3-6Cycloalkenyl group and C3-6Cycloalkyl-C1-6Moieties can be with It is unsubstituted or by RiSubstitution is one or more times；
Or RhWith R10And R11One of and their atoms for being connected can form 4,5,6 or 7 yuan of aromatics saturations together or portion Divide the ring of saturation, it can optionally include 1 or 2 the-O- being selected from ,-NRa- or-S- other hetero atoms, it can be optionally by Ri Substitution is one or more times；
Or RfAnd RgOne of and R10And R11One of and their atoms for being connected can form 3,4,5,6 or 7 yuan of virtues together Race's saturation or fractional saturation ring, it optionally can be selected from-O- ,-NR comprising 1 or 2a- or-S- other hetero atoms, its Can be optionally by RiSubstitution is one or more times；
RiFor：
C1-6Alkyl；
Halo-C1-6Alkyl；
C3-6Cycloalkyl；
Halogen；
Oxo；
Hydroxyl；
Acetyl group；
C1-6Alkyl-carbonyl；
Amino-carbonyl；
Hydroxyl-C1-6Alkyl；
Cyano group；
Cyano group-C1-6Alkyl；
C1-6Alkoxy -C1-6Alkyl；
Carboxyl；Or
C1-6Alkoxy；
RjAnd RkEach stand alone as：
Hydrogen；Or
C1-6Alkyl, it can be unsubstituted or be optionally substituted by halogen one or more times；
Each RmStand alone as：
C1-6Alkyl；
Oxo；
Hydroxyl；
Amino；
C3-6Cycloalkyl；
Amino-C1-6Alkyl；
Hydroxyl-C1-6Alkyl；
Hydroxyl-C1-6Alkenyl；
C1-6Alkoxy carbonyl-C1-6Alkyl；
Halogen；
Cyano group-C1-6Alkyl；
Amino carbonyl-C1-6Alkyl；Or
C1-6Alkoxy carbonyl；
Each RnStand alone as：
C1-6Alkyl；
Oxo；
Hydroxyl；
Amino；
C3-6Cycloalkyl；
Amino-C1-6Alkyl；
Hydroxyl-C1-6Alkyl；
Hydroxyl-C1-6Alkenyl；
C1-6Alkoxy carbonyl-C1-6Alkyl；
Halogen；
Amino carbonyl-C1-6Alkyl；Or
C1-6Alkoxy carbonyl；And
RpFor：
Hydrogen；Or
C1-6Alkyl.
2. the compound of claim 1, wherein m are 1.
3. the compound of claim 1 or 2, wherein n is 0.
4. any one of claim 1-3 compound, wherein A are key.
5. any one of claim 1-4 compound, wherein W are-CH2-。
6. any one of claim 1-5 compound, wherein X1、X2、X3And X4For CRe。
7. any one of claim 1-6 compound, wherein Y are-O- or-CRfRg-。
8. any one of claim 1-7 compound, wherein Z are：Key；-NRp-C1-6Alkylidene；-C(O)-；-C(O) NRp-；-C(O)NRx-C1-6Alkylidene；-NRxC(O)-；-NRx-C1-6Alkylidene；-NRx-；Or-NRxC(O)-C1-6Alkylidene.
9. any one of claim 1-8 compound, wherein Z are：Key；-NRp-C1-6Alkylidene；-C(O)-；-C(O) NRp-；-NRx-C1-6Alkylidene；Or-C (O) NRp-。
10. any one of claim 1-9 compound, wherein Z are key
11. any one of claim 1-10 compound, wherein Het are heteroaryl, it is selected from：Oxazolyl；Isoxazolyl； Pyrazolyl；Triazolyl；Huo oxadiazolyls；Each of which can be unsubstituted or by RmSubstitution is one or more times.
12. any one of claim 1-11 compound, wherein Het are：3H-1,3,4- oxadiazole -2- ketone -5- bases；3- first Base -1,3,4- oxadiazole -2- ketone -5- bases；4H-1,2,4- triazole -3- bases；3H-1,3,4- oxadiazole -2- ketone -5- bases；Pyrazine- 2- bases；5- methyl-isoxazole -3- bases；Isoxazole -3-base；The isoxazole -5-base of 3- oxos-；Oxazole -2- bases；2- methyl isophthalic acids, 2,4- Triazole -3- bases；Oxazole -4- bases；1H- pyrazoles -5- bases；Pyrimidine -2-base；1H- pyrazole-3-yls；1,3,4- oxadiazole -2- formic acid - 5- bases；3- amino-pyrazol -1- bases；Or N- methyl isophthalic acids, 2,4- oxadiazole -5- formamide -3- bases.
13. any one of claim 1-12 compound, wherein R1、R2、R4、R5、R6、R7And R8For hydrogen.
14. any one of claim 1-13 compound, wherein R3For methyl.
15. any one of claim 1-14 compound, wherein RfFor：Hydrogen；Halogen；C1-6Alkyl；Or halo-C1-6Alkyl.
16. any one of claim 1-15 compound, wherein RgFor：Hydrogen；Halogen；C1-6Alkyl；Hydroxyl；C1-6Alkoxy； Or halo-C1-6Alkyl.
17. any one of claim 1-16 compound, wherein RmFor：C1-6Alkyl；Oxo；Hydroxyl；Amino；Or hydroxyl- C1-6Alkyl.
18. the compound of claim 1, wherein the compound is formula III compound,
Wherein：
S is 0-3；And
ReFor：C1-6Alkyl；C1-6Alkoxy；Hydroxyl；Halogen；Hydroxyl-C1-6Alkyl；Or cyano group.
19. composition, the composition includes：
(a) pharmaceutically useful carrier；With
(b) any one of claim 1-18 compound.
20. treating the method for psoriasis, methods described includes giving in the claim 1-18 for the individual effective dose for needing to treat The compound of any one.
21. any one of claim 1-18 compound, for treating psoriasis.
22. the purposes of any one of claim 1-18 compound, for treating psoriasis.
23. the purposes of any one of claim 1-18 compound, for preparing the medicine for the treatment of psoriasis.
24. the invention being outlined above.
CN201680033181.5A 2015-07-08 2016-07-08 Aryl sultam derivative as RORc conditioning agents Pending CN107690431A (en)

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